US8969373B2 - HCV protease inhibitors - Google Patents

HCV protease inhibitors Download PDF

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US8969373B2
US8969373B2 US14/236,468 US201214236468A US8969373B2 US 8969373 B2 US8969373 B2 US 8969373B2 US 201214236468 A US201214236468 A US 201214236468A US 8969373 B2 US8969373 B2 US 8969373B2
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Suoming Zhang
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Shanghai Tangrun Pharmaceuticals Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to a kind of compound having anti-virus activity, more particularly to a kind of hepatitis C virus protease inhibitor.
  • Viral hepatitis can be divided into seven types of A, B, C, D, E, F and G Hepatitis C is the most common one and is a kind of infectious disease targeting liver organs caused by hepatitis C virus (hepatitis C virus, HCV). About 3 percent of the global population has been infected with the hepatitis C virus.
  • Hepatitis C virus is a positive-strand RNA of about 9.6 Kb including 5′ untranslated region (5′-UTR), open reading frame (ORF) and 3′ untranslated region (3′-UTR).
  • ORF is translated into a polypeptide chain which is subsequently processed into at least 10 different proteins including one nucleocapsid protein, two envelope proteins (E1 and E2) and non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B).
  • anti-HCV compounds such as ABT-450, BMS-650032, BI 201335, TMC-435, GS 9256, ACH-1625, MK-7009, etc
  • All of them are designed to target HCV NS3/4A serine protease inhibitors.
  • the drug boceprevir developed by the pharmaceutical giant Merck (Merck) and the drug telaprevir developed by Vertex Pharmaceuticals, Inc. (Vertex) both are designed to target NS3/4A serine protease of HCV, which were approved by U.S. FDA in 2011. Showed clinically is that the cure rate of both drugs combined with standard treatment can be increased to approximately 75%.
  • the first aim of the present invention is to provide an anti-virus compound having the general formula (I), or a pharmaceutically acceptable prodrug, salt or hydrate thereof,
  • Rx and Ry independently is F, Cl, C 1 -C 6 alkyl or C 1 -C 6 alkoxyl
  • Rz is C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 alkylformyl or (C 1 -C 6 alkyl)-SO 2 —.
  • Z 1 is N or CR Z1
  • Z 2 is CR Z2
  • R Z1 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NH 2 , (C 1 -C 6 alkyl)NH or (C 1 -C 6 alkyl) 2 N
  • R Z2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl or heteroaryl
  • Z 1 links with O
  • Z 2 is CH
  • Z 3 is C—Ar
  • Ar is a substituted or unsubstituted aryl or heteroaryl.
  • Rx and Ry independently is F, Cl, C 1 -C 6 alkyl or C 1 -C 6 alkoxyl
  • Rz is C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 alkylformyl or (C 1 -C 6 alkyl)-SO 2 —.
  • R 1 is hydrogen
  • R 3 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, heterocycloalkyl, (C 3 -C 7 cycloalkyl) C 1 -C 4 alkyl, (C 3 -C 7 cycloalkenyl) C 1 -C 4 alkyl, (heterocycloalkyl) C 1 -C 4 alkyl, C 2 -C 6 alkylacyl, (C 1 -C 4 alkyl) 1-2 (C 3 -C 7 ) cycloalkyl or (C 1 -C 6 alkyl) 1-2 amino.
  • the general formula (I) turns into formula (Ib1),
  • Rx and Ry independently is F, Cl, C 1 -C 6 alkyl or C 1 -C 6 alkoxyl
  • Rz is C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 alkylformyl or (C 1 -C 6 alkyl)-SO 2 —.
  • R 1 linking covalently with R 3 together forms a C 5 -C 9 saturated or unsaturated hydrocarbon chain which can be inserted by 0 ⁇ 2 heteroatom(s) independently selected from N, S and O, or which can be substituted by none or more halogen, O, S or —NR p R q , wherein, R p and R q independently is hydrogen or C 1 -C 6 alkyl.
  • a 1 is preferably CH 2 and the general formula (I) turns into formula (Ib2),
  • Rx and Ry independently is F, Cl, C 1 -C 6 alkyl or C 1 -C 6 alkoxyl
  • Rz is C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 alkylformyl or (C 1 -C 6 alkyl)-SO 2 —.
  • the detailed compound is preferably as follows:
  • the second aim of the present invention is to provide a pharmaceutical composition that comprises the compound having the general formula (I) of the present invention and pharmaceutically acceptable carrier(s).
  • the pharmaceutical composition of the present invention can also be used in combination with other anti-virus drugs such as interferon or ribavirin.
  • the third aim of the present invention is to provide a use of the compound of the present invention in preparation of a drug for preventing virus infection or antivirus, wherein, said virus is preferably hepatitis virus, more preferably hepatitis C virus.
  • the forth aim of the present invention is to provide a method where an effective amount of the compound of the present invention is administered to a patient infected with hepatitis virus, more preferably with HCV.
  • Step S 1A Synthesis of 1-(3-amino-benzofuran-2-yl)-ethanone (1A)
  • Step S 1B Synthesis of (E) 2-cinnamoyl-3-amino-benzofuran (1B)
  • Step S 1C Synthesis of 2-phenyl-2,3-dihydrobenzofuron[3,2-b]pyridin-4(1H)-one (1C)
  • Step S 1D Synthesis of 2-phenyl-4-hydroxyl-benzo[4,5]furo[3,2-b]pyridine (1D)
  • Step S 1E Synthesis of 4-chloro-2-phenyl-benzofuro[3,2-b]pyridine (M1)
  • Step S 2B Synthesis of 1-(3-amino-4-chloro-benzothiophen-2-yl)-ethanone (2B)
  • step S 1A The procedure was similar to step S 1A , while the starting material was 2-chloro-6-mercapto-benzonitrile (2A) in stead of 2-hydroxy-benzonitrile.
  • Step S 2C Synthesis of (E) 2-cinnamoyl-3-amino-4-chloro-benzo[b]thiophene (2C)
  • step S 1B The procedure was similar to step S 1B , while the starting material was 2B in stead of 1A.
  • Step S 2D Synthesis of 2-phenyl-9-chloro-2,3-dihydro-benzo[4,5]thieno[3,2-b]pyridin-4(1H)-one (2D)
  • step S 1C The procedure was similar to step S 1C , while the starting material was 2C in stead of 1B.
  • Step S 2E Synthesis of 2-phenyl-9-chloro-4-hydroxyl-benzo[4,5]thieno[3,2-b]pyridine (2E)
  • step S 1D The procedure was similar to step S 1D , while the starting material was 2D in stead of 1C.
  • Step S 2F Synthesis of 4,9-dichloro-2-phenyl-benzo[4,5]thieno[3,2-b]pyridine (M2)
  • step S 1E The procedure was similar to step S 1E , while the starting material was 2E in stead of 1D.
  • step S 2A The procedure was similar to step S 2A , while the starting material was 2-fluoro-benzonitrile in stead of 2,6-dichloro-benzonitrile.
  • Step S 3B Synthesis of 1-(3-amino-benzo[b]thiophen-2-yl)-ethanone (3B)
  • step S 1A The procedure was similar to step S 1A , while the starting material was 2-mercapto-benzonitrile (3A) in stead of 2-hydroxy-benzonitrile.
  • Step S 3C Synthesis of (E)-2-cinnamoyl 3-amino-benzo[b]thiophene (3C)
  • step S 1B The procedure was similar to step S 1B , while the starting material was 3B in stead of 1A.
  • Step S 3D Synthesis of 2-phenyl-2,3-dihydro-benzo[4,5]thieno[3,2-b]pyridin-4(1H)-one (3D)
  • step S 1C The procedure was similar to step S 1C , while the starting material was 2C in stead of 1B.
  • Step S 3E Synthesis of 2-phenyl-4-hydroxyl-benzothieno[3,2-b]pyridine (3E)
  • step S 1D The procedure was similar to step S 1D , while the starting material was 3D in stead of 1C.
  • Step S 3F Synthesis of 4-chloro-2-phenyl-benzothieno[3,2-b]pyridine (M3)
  • step S 1E The procedure was similar to step S 1E , while the starting material was 3E in stead of 1D.
  • Step S 4A Synthesis of 2-hydroxy-5-methoxy-benzaldehyde (4A)
  • Step S 4C Synthesis of 1-(3-amino-5-methoxy-benzofuran-2-yl)-ethanone (4C)
  • step S 1A The procedure was similar to step S 1A , while the starting material was 2-hydroxy-5-methoxy-benzonitrile (4B) in stead of 2-hydroxy-benzonitrile.
  • Step S 4D Synthesis of (E)-2-cinnamoyl-3-amino-5-methoxy-benzofuran (4D)
  • step S 1B The procedure was similar to step S 1B , while the starting material was 4C in stead of 1A.
  • Step S 4E Synthesis of 2-phenyl-8-methoxy-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (4E)
  • step S 1C The procedure was similar to step S 1C , while the starting material was 4D in stead of 1B.
  • Step S 4F Synthesis of 2-phenyl-4-hydroxyl-8-methoxy-benzofuro[3,2-b]pyridine (4F)
  • step S 1D The procedure was similar to step S 1D , while the starting material was 4E in stead of 1C.
  • Step S 4G Synthesis of 4-chloro-8-methoxy-2-phenyl-benzofuro[3,2-b]pyridine (M4)
  • step S 1E The procedure was similar to step S 1E , while the starting material was 4F in stead of 1D.
  • Step S 5B Synthesis of 1-(3-amino-5-chloro-benzofuran-2-yl)-ethanone (5B)
  • step S 1A The procedure was similar to step S 1A , while the starting material was 5-chloro-2-hydroxy-benzonitrile (5A) in stead of 2-hydroxy-benzonitrile.
  • Step S 5C Synthesis of (E)-2-cinnamoyl-3-amino-5-chloro-benzofuran (5C)
  • step S 1B The procedure was similar to step S 1B , while the starting material was 5B in stead of 1A.
  • Step S 5D Synthesis of 2-phenyl-8-chloro-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (5D)
  • step S 1C The procedure was similar to step S 1C , while the starting material was 5C in stead of 1B.
  • Step S 5E Synthesis of 2-phenyl-8-chloro-4-hydroxyl-benzofuro[3,2-b]pyridine (5E)
  • step S 1D The procedure was similar to step S 1D , while the starting material was 5D in stead of 1C.
  • Step S 5F Synthesis of 4,8-dichloro-2-phenyl-benzo[4,5]furo[3,2-b]pyridine (M5)
  • step S 1E The procedure was similar to step S 1E , while the starting material was 5E in stead of 1D.
  • Step S 6A Synthesis of 1-(3-amino-5-bromo-benzofuran-2-yl)-ethanone (6A)
  • Step S 6B Synthesis of (Z)-2-cinnamoyl-3-amino-5-bromo-benzofuran (6B)
  • Step S 6C Synthesis of 8-bromo-2-phenyl-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (6C)
  • Step S 6D Synthesis of 4-hydroxyl-8-bromo-2-phenyl-benzofuro[3,2-b]pyridine (6D)
  • Step S 6E Synthesis of 8-bromo-4-chloro-2-phenyl-benzofuro[3,2-b]pyridine (M6)
  • Step S 7A Synthesis of 2-chloro-3,6-dihydroxy-benzaldehyde (7A)
  • Step S 7B Synthesis of (E)-2-chloro-3,6-dihydroxy-benzaldehyde oxime (7B)
  • Step S 7C Synthesis of 2-chloro-3-cyano-1,4-diacetoxy-benzene (7C)
  • Step S 7D Synthesis of acetic acid 2-chloro-3-cyano-4-hydroxy-phenyl ester (7D)
  • Step S 7E Synthesis of 2-acetyl-3-amino-4-chloro-5-acetoxyl-benzofuran (7E)
  • Step S 7F Synthesis of 2-acetyl-3-amino-4-chloro-5-hydroxy-benzofuran (7F)
  • Step S 7G Synthesis of 2-acetyl-3-amino-4-chloro-5-methoxyl-benzofuran (7G)
  • Step S 8A Synthesis of 2-cinnamoyl-3-amino-4-chloro-5-methoxy-benzofuran (8A)
  • Step S 8B Synthesis of 9-chloro-8-methoxy-2-phenyl-2,3-dihydrobenzofuro[3,2-b]pyridin-4(1H)-one (8B)
  • Step S 8C Synthesis of 4-hydroxyl-9-chloro-8-methoxy-2-phenyl-benzofuro[3,2-b]pyridine (8C)
  • Step S 8D Synthesis of 4,9-dichloro-8-methoxy-2-phenyl-benzofuro[3,2-b]pyridine (M8)
  • Step S 9A Synthesis of (E)-1-(3-amino-4-chloro-5-methoxy-benzofuran-2-yl)-3-(2-isopropyl-thiazol-5-yl)-2-propen-1-one (9A)
  • Step S 9B Synthesis of 9-chloro-2-(2-isopropylthiazol-5-yl)-8-methoxy-1,2-dihydro-benzofuro[3,2-b]pyridin-4-one (9B)
  • Step S 9C Synthesis of 4-hydroxyl-9-chloro-2-(2-isopropyl-thiazol-5-yl)-8-methoxy-benzofuro[3,2-b]pyridine (9C)
  • Step S 9D Synthesis of 4,9-dichloro-2-(2-isopropyl-thiazol-5-yl)-8-methoxy-benzofuro[3,2-b]pyridine (M9)
  • Step S 10A Synthesis of 1-(3-amino-4-chloro-5-methoxy-benzofuran-2-yl)-3-(2-isopropyl-thiazol-4-yl)-2-propen-1-one (10A)
  • Step S 10B Synthesis of 9-chloro-2-(2-isopropyl-thiazol-4-yl)-8-methoxy-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (10B)
  • Step S 10C Synthesis of 4-hydroxyl-9-chloro-2-(2-isopropyl-thiazol-4-yl)-8-methoxy-benzofuro[3,2-b]pyridine (10C)
  • Step S 10D Synthesis of 4,9-dichloro-2-(2-isopropyl-thiazol-4-yl)-8-methoxy-benzofuro[3,2-b]pyridine (M10)
  • Step S 11A Synthesis of isobutyryl-thiourea (11A)
  • Step S 11B Synthesis of 2-isobutyrylamino-thiazole-4-carboxylic acid ethyl ester (11B)
  • Step S 11C Synthesis of 2-isobutyrylamino-thiazole-4-methanol (11C)
  • Step S 11D Synthesis of N-(4-formyl-thiazol-2-yl)-isobutyramide (11D)
  • Step S 11E Synthesis of N- ⁇ 4-[3-(3-amino-4-chloro-5-methoxy-benzofuran-2-yl)-3-oxo-propenyl]-thiazol-2-yl ⁇ -isobutyramide (11E)
  • Step S 11F Synthesis of 9-chloro-2-(2-isobutyrylamino-thiazole-4-yl)-8-methoxy-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (11F)
  • Step S 11G Synthesis of 4-hydroxyl-9-chloro-2-(2-isobutyrylamino-thiazole-4-yl)-8-methoxy-benzofuro[3,2-b]pyridine (11G)
  • Step S 11H Synthesis of 4,9-dichloro-2-(2-isobutyrylamino-thiazole-4-yl)-8-methoxy-2,3-dihydro-benzofuro[3,2-b]pyridine (M11)
  • Step S 12A Synthesis of 2-bromo-3,6-dihydroxy-benzaldehyde (12A)
  • Step S 12B Synthesis of 2-bromo-3,6-dihydroxy-benzaldehyde oxime (12B)
  • Step S 12C Synthesis of 2-bromo-3-cyano-1,4-diacetoxylbenzene (12C)
  • Step S 12D Synthesis of 2-bromo-3-cyano-4-hydroxy-phenyl acetate (12D)
  • Step S 12E Synthesis of 2-acetyl-3-amino-4-bromo-5-acetoxyl-benzofuran (12E)
  • Step S 12F Synthesis of 2-acetyl-3-amino-4-bromo-5-hydroxy-benzofuran (12F)
  • Step S 12G Synthesis of 2-acetyl-3-amino-4-bromo-5-methoxy-benzofuran (12G)
  • Step S 13A Synthesis of 2-cinnamoyl-3-amino-4-bromo-5-methoxy-benzofuran (13A)
  • Step S 13B Synthesis of 9-bromo-8-methoxy-2-phenyl-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (13B)
  • Step S 13C Synthesis of 4-hydroxyl-9-bromo-8-methoxy-2-phenyl-benzofuro[3,2-b]pyridine (13C)
  • Step S 13D Synthesis of 9-bromo-4-chloro-8-methoxy-2-phenyl-benzofuro[3,2-b]pyridine (M13)
  • Step S 14A Synthesis of (E)-1-(3-amino-4-bromo-5-methoxy-benzofuran-2-yl)-3-(2-isopropyl-thiazol-5-yl)-2-propen-1-one (14A)
  • Step S 14B Synthesis of 9-bromo-2-(2-isopropyl-thiazol-5-yl)-8-methoxy-1,2-dihydro-benzofuro[3,2-b]pyridin-4-one (14B)
  • Step S 14C Synthesis of 4-hydroxyl-9-bromo-2-(2-isopropyl-thiazol-5-yl)-8-methoxy-dibenzofuran (14C)
  • Step S 14D Synthesis of 9-bromo-4-chloro-2-(2-isopropyl-thiazol-5-yl)-8-methoxy-benzofuro[3,2-b]pyridine (M14)
  • Step S 15A Synthesis of 1-(3-amino-4-bromo-5-methoxy-benzofuran-2-yl)-3-(2-isopropyl-thiazol-4-yl)-2-propen-1-one (15A)
  • Step S 15B Synthesis of 9-bromo-2-(2-isopropyl-thiazol-4-yl)-8-methoxy-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (15B)
  • Step S 15C Synthesis of 4-hydroxyl-9-bromo-2-(2-isopropyl-thiazol-4-yl)-8-methoxy-benzofuro[3,2-b]pyridine (15C)
  • Step S 15D Synthesis of 9-bromo-4-chloro-2-(2-isopropyl-thiazol-4-yl)-8-methoxy-benzofuro[3,2-b]pyridine (M15)
  • Step S 16A Synthesis of 1-(3-amino-4-bromo-5-methoxy-benzofuran-2-yl)-3-(2-isobutyrylamino-thiazole-4-yl)-2-propen-1-one (16A)
  • Step S 16B Synthesis of 9-bromo-2-(2-isobutyrylamino-thiazole-4-yl)-8-methoxy-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (16B)
  • Step S 16C Synthesis of 4-hydroxyl-9-bromo-2-(2-isobutyrylamino-thiazole-4-yl)-8-methoxy-benzofuro[3,2-b]pyridine (16C)
  • Step S 16D Synthesis of 9-bromo-4-chloro-2-(2-isobutyrylamino-thiazole-4-yl)-8-methoxy-benzofuro[3,2-b]pyridine (M16)
  • step S 3A The procedure was similar to step S 3A , while the starting material was 2,4-difluoro-benzonitrile in stead of 2-fluoro-benzonitrile.
  • Step S 17B Synthesis of 1-(3-amino-6-fluoro-benzo[b]thiophen-2-yl)-ethanone (17B)
  • step S 3B The procedure was similar to step S 3B , while the starting material was 17A in stead of 3A.
  • Step S 17C Synthesis of (E)-2-cinnamoyl-3-amino-6-fluoro-benzo[b]thiophene (17C)
  • step S 3C The procedure was similar to step S 3C , while the starting material was 17B in stead of 3B.
  • Step S 17D Synthesis of 2-phenyl-7-fluoro-2,3-dihydro-benzothieno[3,2-b]pyridin-4(1H)-one (17D)
  • step S 3D The procedure was similar to step S 3D , while the starting material was 17C in stead of 3C.
  • Step S 17E Synthesis of 2-phenyl-7-fluoro-4-hydroxyl-benzothieno[3,2-b]pyridine (17E)
  • step S 3E The procedure was similar to step S 3E , while the starting material was 17D in stead of 3D.
  • Step S 17F Synthesis of 4-chloro-7-fluoro-2-phenyl-benzothieno[3,2-b]pyridine (M17)
  • step S 3F The procedure was similar to step S 3F , while the starting material was 17E in stead of 3E.
  • Step S 18A Synthesis of 2-carboxyl-phenyl acetic acid (18A)
  • Step S 18B Synthesis of 2-carboxymethyl-5-nitro-benzoic acid (18B)
  • Step S 18C Synthesis of 2-methoxycarbonylmethyl-5-nitro-benzoic acid methyl ester (18C)
  • Step S 18D Synthesis of 2-methoxycarbonylmethyl-5-amino-benzoic acid methyl ester (18D)
  • Step S 18E Synthesis of 4-chloro-2-methoxycarbonyl-phenyl acetic acid methyl ester (18E)
  • 5-amino-2-methoxycarbonylmethyl-benzoic acid methyl ester (5 g, 22.4 mmol) was dissolved in hydrochloric acid (50 mL). To the solution was added dropwise aq.NaNO 2 (1.7 g, 24.6 mmol) at below 5° C. After addition completed, the color became maroon. Then CuCl (2.4 g, 24.6 mmol) solution was added to the reaction mixture. The reaction mixture was reacted at below 5° C. for 1 hour. The reaction mixture was extracted with dichloromethane.
  • Step S 19A Synthesis of 2-(4-chloro-2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (19A)
  • Step S 19B Synthesis of 3-chloro-benzofuro[3,2-c]isoquinoline-5-ol (19B)
  • Step S 19C Synthesis of 3,5-dichloro-benzofuro[3,2-c]isoquinoline (M19)
  • Step S 20A Synthesis of 2-(4-bromo-2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (20A)
  • step S 19A The procedure was similar to step S 19A , while the starting material was 5-bromo-2-methoxycarbonylmethyl-benzoic acid methyl ester (the procedure of this compound was similar to 5-chloro-2-methoxycarbonylmethyl-benzoic acid methyl ester, while the starting material was CuBr in stead of CuCl) in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester.
  • Step S 20B Synthesis of 5-hydroxyl-3-bromo-benzofuro[3,2-c]isoquinoline (20B)
  • step S 19B The procedure was similar to step S 19B , while the starting material was 20A in stead of 19A.
  • Step S 20C Synthesis of 3-bromo-5-chloro-benzofuro[3,2-c]isoquinoline (M20)
  • step S 19C The procedure was similar to step S 19C , while the starting material was 20B in stead of 19B.
  • Step S 21A Synthesis of 2-(2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (21A)
  • step S 19A The procedure was similar to step S 19A , while the starting material was 2-methoxycarbonylmethyl-benzoic acid methyl ester (commercialized) in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester (18E).
  • Step S 21B Synthesis of 5-hydroxyl-8-methoxy-benzofuro[3,2-c]isoquinoline (21B)
  • step S 19B The procedure was similar to step S 19B , while the starting material 19A and 2-hydroxy-benzonitrile were replaced with 21A and 2-hydroxy-5-methoxy-benzonitrile, respectively.
  • Step S 21C Synthesis of 8-methoxy-5-chloro-benzofuro[3,2-c]isoquinoline (M21)
  • step S 19C The procedure was similar to step S 19C , while the starting material was 21B in stead of 19B.
  • Step S 22A Synthesis of 2-(2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (22A)
  • step S 19A The procedure was similar to step S 19A , while the starting material was 2-methoxycarbonylmethyl-benzoic acid methyl ester (commercialized) in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester (18E).
  • Step S 22B Synthesis of 5-hydroxyl-benzofuro[3,2-c]isoquinoline 1 (22B)
  • step S 19B The procedure was similar to step S 19B , while the starting material was 22A in stead of 19A.
  • Step S 22C Synthesis of 5-chloro-benzofuro[3,2-c]isoquinoline (M22)
  • step S 19C The procedure was similar to step S 19C , while the starting material was 22B in stead of 19B.
  • Step S 23A Synthesis of 2-(2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (23A)
  • step S 19A The procedure was similar to step S 19A , while the starting material was 2-methoxycarbonylmethyl-benzoic acid methyl ester (commercialized) in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester (18E).
  • Step S 23B Synthesis of 5-hydroxyl-benzothieno[3,2-c]isoquinoline (23B)
  • step S 19B The procedure was similar to step S 19B , while the starting material was 23A in stead of 19A, and used 2-mercapto-benzonitrile in stead of 2-hydroxy-benzonitrile.
  • Step S 23C Synthesis of 5-chloro-benzothieno[3,2-c]isoquinoline (M23)
  • step S 19C The procedure was similar to step S 19C , while the starting material was 23B in stead of 19B.
  • Step S 24A Synthesis of 2-(2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (24A)
  • step S 19A The procedure was similar to step S 19A , while the starting material was 2-methoxycarbonylmethyl-benzoic acid methyl ester in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester (18E).
  • Step S 24B Synthesis of 5-hydroxyl-8-chloro-benzofuro[3,2-c]isoquinoline (24B)
  • step S 19B The procedure was similar to step S 19B , while the starting material was 24A in stead of 19A, and used 5-chloro-2-hydroxy-benzonitrile in stead of 2-hydroxy-benzonitrile.
  • Step S 24C Synthesis of 5,8-dichloro-benzofuro[3,2-c]isoquinoline (M24)
  • step S 19C The procedure was similar to step S 19C , while the starting material was 24B in stead of 19B.
  • Step S 25A Synthesis of 2-(4-methoxyl-2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (25A)
  • step S 19A The procedure was similar to step S 19A , while the starting material was 5-methoxyl-2-methoxycarbonylmethyl-benzoic acid methyl ester (commercialized) in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester (18E).
  • Step S 25B Synthesis of 5-hydroxyl-3-methoxy-benzofuro[3,2-c]isoquinoline (25B)
  • step S 19B The procedure was similar to step S 19B , while the starting material was 25A in stead of 19A.
  • Step S 25C Synthesis of 3-methoxy-5-chloro-benzofuro[3,2-c]isoquinoline (M25)
  • step S 19C The procedure was similar to step S 19C , while the starting material was 25B in stead of 19B.
  • Step S 26A Synthesis of 2-(4-chloro-2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (26A)
  • Step S 26B Synthesis of 5-hydroxyl-3-chloro-8-methoxy-benzofuro[3,2-c]isoquinoline (26B)
  • step S 19B The procedure was similar to step S 19B , while the starting material was 2-hydroxy-5-methoxy-benzonitrile in stead of 2-hydroxy-benzonitrile.
  • Step S 26C Synthesis of 3,5-dichloro-8-methoxy-benzofuro[3,2-c]isoquinoline (M26)
  • step S 19C The procedure was similar to step S 19C , while the starting material was 26B in stead of 19B.
  • Step S 27A Synthesis of 2-(4-chloro-2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (27A)
  • Step S 27B Synthesis of 3,8-dichloro-5-hydroxyl-benzofuro[3,2-c]isoquinoline 1 (27B)
  • step S 19B The procedure was similar to step S 19B , while the starting material was 5-chloro-2-hydroxy-benzonitrile in stead of 2-hydroxy-benzonitrile.
  • Step S 27C Synthesis of 3,5,8-trichloro-benzofuro[3,2-c]isoquinoline (M27)
  • step S 19C The procedure was similar to step S 19C , while the starting material was 27B in stead of 19B.
  • Step S 28A Synthesis of 2-(4-methoxyl-2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (28A)
  • step S 19A The procedure was similar to step S 19A , while the starting material was 5-methoxy-2-methoxycarbonylmethyl-benzoic acid methyl ester (commercialized) in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester (18E).
  • Step S 28B Synthesis of 5-hydroxyl-3-methoxy-8-chloro-benzofuro[3,2-c]isoquinoline (28B)
  • step S 19B The procedure was similar to step S 19B , while the starting material was 28A in stead of 19A, and used 5-chloro-2-hydroxy-benzonitrile in stead of 2-hydroxy-benzonitrile.
  • Step S 28C Synthesis of 3-methoxy-5,8-dichloro-benzofuro[3,2-c]isoquinoline (M28)
  • step S 19C The procedure was similar to step S 19C , while the starting material was 28B in stead of 19B.
  • Step S 29A Synthesis of 2-(2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (29A)
  • step S 19A The procedure was similar to step S 19A , while the starting material was 2-methoxycarbonylmethyl-benzoic acid methyl ester in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester (18E).
  • Step S 29B Synthesis of 5-hydroxyl-9-fluoro-benzothieno[3,2-c]isoquinoline (29B)
  • step S 19B The procedure was similar to step S 19B , while the starting material was 29A in stead of 19A, and used 4-fluoro-2-mercapto-benzonitrile in stead of 2-hydroxy-benzonitrile.
  • Step S 29C Synthesis of 5-chloro-9-fluoro-benzothieno[3,2-c]isoquinoline (M29)
  • step S 19C The procedure was similar to step S 19C , while the starting material was 29B in stead of 19B.
  • HATU o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • N,N-diisopropyl ethylamine 0.2 mmol
  • Huh7.5.1cells Huh 7.5.1 cells were seeded at a 96-well plate with 37 and 5% CO 2 for 24 hours incubation.
  • Virus infection Using the J399EM virus supernatants (moi ⁇ 0.1) to infect Huh7.5.1cells. At the same time, the no virus infected cell will be set up as the control. After 8 hours virus infection, the virus will be washed out with PBS.
  • the test dose of sample is starting from 25 nM or 400 nM, with quarter dilution, 5 doses of sample will be added in the test wells, respectively, then continued for 72 hours incubation.
  • HCV-EGFP fluorescence detection After samples treatment for 72 hours, the autofluorescence of HCV-EGFP were measured by the luminometer with excitation of 488 nm, and emission of 516 nm. The related fluorescence unit (RFU) of samples will be read out and used for calculating the inhibitory rates of compounds in HCV replication.
  • REU fluorescence unit
  • HCV replicon cell-line The Huh7 cells were transfected with pSGR-399LM replicon DNA and cultured in the DMEM containing 10% FBS and 0.5 mg/mL G418. The cells were split at 1:3 to 1:5 every 3-4 days. The transfected cells were seeded in 96-well plates and cultured at 37° C., 5% CO 2 for 24 hr.
  • Fluorescence detection After 72 hr treatment with sample, the cells were lysed and added with Renilla luciferase substrate to detect luminescent signal. The relative luminescent unit (RLU) in the luminometer was read out and used to calculate the inhibition rate of HCV.
  • RLU relative luminescent unit
  • mice Twenty healthy male Sprague-Dawley (SD) rats with body weight of 200-220 g were divided into 5 groups randomly and each group contains 4 rats. Before the experiment, rats were fasted for 12 h with free access to water.
  • the compounds were prepared with 0.5% CMC-Na containing 1% Tween 80. The dose volume was 10 mL/kg.
  • the rats were afforded unlimited access to food after 2 h of dosing 0.3 mL of blood samples were collected at 0.25 h, 0.5 h, 1.0 h, 2.0 h, 3.0 h, 5.0 h, 7.0 h, 9.0 h, and 24.0 h, respectively, from postocular venous plexes of the rat.
  • the blood samples were placed in heparin-containing tubes and immediately centrifuged at 11000 rpm for 5 min. Plasma was separated and refrigerated at ⁇ 20° C. until analysis. LC-MS/MS methods were used to quantify plasma concentrations of the compound Ik. The pharmacokinetic parameters obtained are shown in Table 3.
  • the compounds of this invention showed satisfied pharmacokinetic behaviour.
  • Compound I18 was orally administered to SD rats at 10 mg/kg.
  • the peak plasma concentration was at 1.7 ⁇ 0.6 h, with C max of 623 ⁇ 60.7 ng/mL, and the area under plasma concentration-time curves AUC 0-t was 3218.5 ⁇ 336.4 ng ⁇ h/mL, AUC 0- ⁇ was 3266.8 ⁇ 303.2 ng ⁇ h/mL.
  • the elimination half-life t 1/2 was 3.8 ⁇ 1.0 h.
  • the absolute bioavailability F approached to 36.1%.
  • the compounds of the present invention have the excellent activity of anti-hepatitis C virus.
  • the value EC 50 of the desired compounds for HCV replicon system (pSGR-399LM+Huh7.5) all are lesser than 1000 nM. A majority of compounds are lesser than 100 nM.
  • the value EC 50 of the compounds for HCV infected human hepatocellular carcinoma cells (Huh7.5.1) in vitro all are lesser than 1000 nM also. And the compounds of this invention showed satisfied pharmacokinetic behaviour also.

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Abstract

A compound of general formula (I);
Figure US08969373-20150303-C00001
A is O, S, CH, NH or NR′, when O links with Z3, Z1 is N or CRZ1, Z2 is CRZ2, when Z1 links with O, Z2 is CH, Z3 is C—Ar; Ra, Rb, Rc and Rd independently is H, OH, halogen or —Y1—Rm; A1 is NH or CH2; R1′ is alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl; A2 is N, O or linking bond; R1 is hydrogen, or, R1 linking covalently with R3 forms C5-C9 saturated or unsaturated hydrocarbon chain substituted by O or N; R3 is alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted by cycloalkyl etc; R4 is alkoxy-CO, alkyl-NHCO, (alkyl)2NCO, or formyl substituted by aryl, cycloalkyl, heterocycloalkyl.

Description

FIELD OF THE INVENTION
The invention relates to a kind of compound having anti-virus activity, more particularly to a kind of hepatitis C virus protease inhibitor.
BACKGROUND OF THE INVENTION
Viral hepatitis can be divided into seven types of A, B, C, D, E, F and G Hepatitis C is the most common one and is a kind of infectious disease targeting liver organs caused by hepatitis C virus (hepatitis C virus, HCV). About 3 percent of the global population has been infected with the hepatitis C virus.
Hepatitis C virus (HCV) is a positive-strand RNA of about 9.6 Kb including 5′ untranslated region (5′-UTR), open reading frame (ORF) and 3′ untranslated region (3′-UTR). ORF is translated into a polypeptide chain which is subsequently processed into at least 10 different proteins including one nucleocapsid protein, two envelope proteins (E1 and E2) and non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B).
At present, there are about 17 anti-HCV compounds (such as ABT-450, BMS-650032, BI 201335, TMC-435, GS 9256, ACH-1625, MK-7009, etc) which have been into the stage of the pre-clinical and clinical development. All of them are designed to target HCV NS3/4A serine protease inhibitors. For example, the drug boceprevir developed by the pharmaceutical giant Merck (Merck) and the drug telaprevir developed by Vertex Pharmaceuticals, Inc. (Vertex), both are designed to target NS3/4A serine protease of HCV, which were approved by U.S. FDA in 2011. Showed clinically is that the cure rate of both drugs combined with standard treatment can be increased to approximately 75%.
Nevertheless, these drugs are just the beginning. Researchers are developing drugs targeting to more than one biological characteristic of hepatitis C virus. These drugs by combined administration are expected to solve the drug-resistant problem of HCV.
SUMMARY OF THE INVENTION
The first aim of the present invention is to provide an anti-virus compound having the general formula (I), or a pharmaceutically acceptable prodrug, salt or hydrate thereof,
Figure US08969373-20150303-C00002
wherein,
  • A is O, S, CH, NH or NR′, wherein, R′ is C1-C6 alkyl substituted or unsubstituted by halogen which includes 0˜3 heteroatom(s) of O, S or N.
  • Ra, Rb, Rc and Rd independently is H, OH, halogen or —Y1—Rm, Y1 is linking bond, O, S, SO, SO2 or NRn; Rm is hydrogen, or, Rm is an unsubstituted substituent or one substituted by 1˜3 Rm′ which is selected from the following group: (C1-C8) alkyl, N≡C—(C1-C6) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) cycloalkyl, (C3-C7 cycloalkyl) (C1-C6) alkyl, and 5˜6 membered aryl or heteroaryl including 0˜2 heteroatom(s) independently selected from N, O, S;
  • Rn is H, (C1-C6) alkyl or (C3-C6) cycloalkyl. Wherein, Rm′ is a substituent selected from the following group: halogen, (C1-C6) alkyl substituted optionally by (C1-C6)alkyl-O— or (C3-C6)cycloalkyl-O—, (C1-C6) haloalkyl, (C3-C7)cycloalkyl, (C1-C6)alkyl-O—, heteroaryl, —NH2, (C1-C4 alkyl)NH— and (C1-C4 alkyl)2N—.
  • A1 is NH or CH2.
  • A2 is N, O or linking bond.
  • R1′ is an unsubstituted substituent or one substituted by 1 to more R1″ which is selected from the following group: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, (aryl) C1-C2 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl) C1-C2 alkyl, C3-C7 cycloalkenyl, (C3-C7 cycloalkenyl) C1-C2 alkyl, heterocycloalkyl, (heterocycloalkyl) C1-C2 alkyl, C5-C10 heteroaryl and (C5-C10 heteroaryl) C1-C2 alkyl;
  • R1″ is a substituent selected from the following group: halogen, OH, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, —NH2, (C1-C6 alkyl)-NH— and —N(C1-C6 alkyl)2;
    preferably, R1′ is
Figure US08969373-20150303-C00003
  • R1 is hydrogen; or; R1 linking covalently with R3 together forms a C5-C9 saturated or unsaturated hydrocarbon chain which can be inserted by 0˜2 heteroatom(s) independently selected from N, S and O, or which can be substituted by none or more halogen, O, S or —NRpRq, wherein, Rp and Rq independently is hydrogen or C1-C6 alkyl; preferably, R1 linking covalently with R3 together forms a C5 alkane chain.
  • R3 is C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, heterocycloalkyl, (C3-C7 cycloalkyl) C1-C4 alkyl, (C3-C7 cycloalkenyl) C1-C4 alkyl, (heterocycloalkyl) C1-C4 alkyl, C2-C6 alkylacyl, (C1-C4 alkyl)1-2 (C3-C7) cycloalkyl or (C1-C6 alkyl)1-2 amino.
  • R4 is C1-C10 alkoxycarbonyl, (C1-C10 alkyl)-NHCO, (C1-C10 alkyl)2NCO, aryl, heteroaryl or formyl substituted by 3˜7 membered cycloalkyl, heterocycloalkyl or cycloalkoxy, which may be unsubstituted or substituted by 1 to more R4′; wherein, R4′ is a substituent selected from the following group: halogen, OH, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, —NH2, (C1-C6 alkyl)-NH— and —N(C1-C6 alkyl)2, (C1-C6 alkyl)-SO2—;
    preferably, R4 is
Figure US08969373-20150303-C00004
wherein, Rx and Ry independently is F, Cl, C1-C6 alkyl or C1-C6 alkoxyl, Rz is C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 alkylformyl or (C1-C6 alkyl)-SO2—.
When Z3 links with O, Z1 is N or CRZ1, Z2 is CRZ2, wherein, RZ1 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, NH2, (C1-C6 alkyl)NH or (C1-C6 alkyl)2N, RZ2 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, aryl or heteroaryl; or RZ1, RZ2 with carbon atoms linking with them together form a substituted or unsubstituted ring;
when Z1 links with O, Z2 is CH, Z3 is C—Ar, Ar is a substituted or unsubstituted aryl or heteroaryl.
In one preferable embodiment of the present invention, when Z3 links with O, preferably, RZ1, RZ2 with carbon atoms linking with them together form a 6 membered aromatic ring substituted by Re, Rf, Rg and Rh, shown in formula (Ia),
Figure US08969373-20150303-C00005
In formula (Ia),
  • A is O, S, CH, NH or NR′, wherein, R′ is C1-C6 alkyl substituted or unsubstituted by halogen which includes 0˜3 heteroatom(s) of O, S or N.
  • Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh independently is H, OH, halogen or —Y1—Rm, Y1 is linking bond, O, S, SO, SO2 or NRn; Rm is hydrogen, or, Rm is an unsubstituted substituent or one substituted by 1˜3 Rm′ which is selected from the following group: (C1-C8) alkyl, N≡C—(C1-C6) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) cycloalkyl, (C3-C7 cycloalkyl) (C1-C6) alkyl, and 5˜6 membered aryl or heteroaryl including 0˜2 heteroatom(s) independently selected from N, O, S; Rn is H, (C1-C6) alkyl or (C3-C6) cycloalkyl. Wherein, Rm′ is a substituent selected from the following group: halogen, (C1-C6) alkyl substituted optionally by (C1-C6)alkyl-O— or (C3-C6)cycloalkyl-O—, (C1-C6) haloalkyl, (C3-C7)cycloalkyl, (C1-C6)alkyl-O—, heteroaryl, —NH2, (C1-C4 alkyl)NH— and (C1-C4 alkyl)2N—.
  • A1 is NH or CH2.
  • A2 is N, O or linking bond.
  • R1′ is an unsubstituted substituent or one substituted by 1 to more R1″ which is selected from the following group: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, (aryl) C1-C2 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl) C1-C2 alkyl, C3-C7 cycloalkenyl, (C3-C7 cycloalkenyl) C1-C2 alkyl, heterocycloalkyl, (heterocycloalkyl) C1-C2 alkyl, C5-C10 heteroaryl and (C5-C10 heteroaryl) C1-C2 alkyl;
  • R1″ is a substituent selected from the following group: halogen, OH, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, —NH2, (C1-C6 alkyl)-NH— and —N(C1-C6 alkyl)2;
    preferably, R1′ is
Figure US08969373-20150303-C00006
  • R1 is hydrogen; or; R1 linking covalently with R3 together forms a C5-C9 saturated or unsaturated hydrocarbon chain which can be inserted by 0˜2 heteroatom(s) independently selected from N, S and O, or which can be substituted by none or more halogen, O, S or —NRpRq, wherein, Rp and Rq independently is hydrogen or C1-C6 alkyl; preferably, R1 linking covalently with R3 together forms a C5 alkane chain.
  • R3 is C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, heterocycloalkyl, (C3-C7 cycloalkyl) C1-C4 alkyl, (C3-C7 cycloalkenyl) C1-C4 alkyl, (heterocycloalkyl) C1-C4 alkyl, C2-C6 alkylacyl, (C1-C4 alkyl)1-2 (C3-C7) cycloalkyl or (C1-C6 alkyl)1-2 amino.
  • R4 is C1-C10 alkoxycarbonyl, (C1-C10 alkyl)-NHCO, (C1-C10 alkyl)2NCO, aryl, heteroaryl or formyl substituted by 3˜7 membered cycloalkyl, heterocycloalkyl or cycloalkoxy, which may be unsubstituted or substituted by 1 to more R4′; wherein, R4′ is a substituent selected from the following group: halogen, OH, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, —NH2, (C1-C6 alkyl)-NH— and —N(C1-C6 alkyl)2, (C1-C6 alkyl)-SO2—;
    preferably, R4 is
Figure US08969373-20150303-C00007
wherein, Rx and Ry independently is F, Cl, C1-C6 alkyl or C1-C6 alkoxyl, Rz is C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 alkylformyl or (C1-C6 alkyl)-SO2—.
In second preferably embodiment of the present invention, when Z1 links with O, preferably, R1 is hydrogen, R3 is C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, heterocycloalkyl, (C3-C7 cycloalkyl) C1-C4 alkyl, (C3-C7 cycloalkenyl) C1-C4 alkyl, (heterocycloalkyl) C1-C4 alkyl, C2-C6 alkylacyl, (C1-C4 alkyl)1-2(C3-C7) cycloalkyl or (C1-C6 alkyl)1-2 amino. In this case, the general formula (I) turns into formula (Ib1),
Figure US08969373-20150303-C00008
In formula (Ib1),
  • Ar is a substituted or unsubstituted aryl or heteroaryl, preferably, Ar is a 6 membered aryl or a 5˜6 membered heteroaryl which is substituted optionally by 1 or more RAr; wherein, RAr is selected from the following substituent group: halogen, amino, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 hydroxyalkyl and (C1-C6) alkylamido.
  • A is O, S, CH, NH or NR′, wherein, R′ is C1-C6 alkyl substituted or unsubstituted by halogen which includes 0˜3 heteroatom(s) of O, S or N.
  • Ra, Rb, Rc and Rd independently is H, OH, halogen or —Y1—Rm, Y1 is linking bond, O, S, SO, SO2 or NRn; Rm is hydrogen, or, Rm is an unsubstituted substituent or one substituted by 1˜3 Rm′ which is selected from the following group: (C1-C8) alkyl, N≡C—(C1-C6) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) cycloalkyl, (C3-C7 cycloalkyl) (C1-C6) alkyl, and 5˜6 membered aryl or heteroaryl including 0˜2 heteroatom(s) independently selected from N, O, S;
  • Rn is H, (C1-C6) alkyl or (C3-C6) cycloalkyl. Wherein, Rm′ is a substituent selected from the following group: halogen, (C1-C6) alkyl substituted optionally by (C1-C6)alkyl-O— or (C3-C6)cycloalkyl-O—, (C1-C6) haloalkyl, (C3-C7)cycloalkyl, (C1-C6)alkyl-O—, heteroaryl, —NH2, (C1-C4 alkyl)NH— and (C1-C4 alkyl)2N—.
  • A1 is NH or CH2.
  • A2 is N, O or linking bond.
  • R1′ is an unsubstituted substituent or one substituted by 1 to more R1″ which is selected from the following group: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, (aryl) C1-C2 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl) C1-C2 alkyl, C3-C7 cycloalkenyl, (C3-C7 cycloalkenyl) C1-C2 alkyl, heterocycloalkyl, (heterocycloalkyl) C1-C2 alkyl, C5-C10 heteroaryl and (C5-C10 heteroaryl) C1-C2 alkyl;
  • R1″ is a substituent selected from the following group: halogen, OH, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, —NH2, (C1-C6 alkyl)-NH— and —N(C1-C6 alkyl)2;
    preferably, R1′ is
Figure US08969373-20150303-C00009
  • R4 is C1-C10 alkoxycarbonyl, (C1-C10 alkyl)-NHCO, (C1-C10 alkyl)2NCO, aryl, heteroaryl or formyl substituted by 3˜7 membered cycloalkyl, heterocycloalkyl or cycloalkoxy, which may be unsubstituted or substituted by 1 to more R4′; wherein, R4′ is a substituent selected from the following group: halogen, OH, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, —NH2, (C1-C6 alkyl)-NH— and —N(C1-C6 alkyl)2, (C1-C6 alkyl)-SO2—;
    preferably, R4 is
Figure US08969373-20150303-C00010
wherein, Rx and Ry independently is F, Cl, C1-C6 alkyl or C1-C6 alkoxyl, Rz is C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 alkylformyl or (C1-C6 alkyl)-SO2—.
In another preferably embodiment of the present invention, when Z1 links with O, preferably, R1 linking covalently with R3 together forms a C5-C9 saturated or unsaturated hydrocarbon chain which can be inserted by 0˜2 heteroatom(s) independently selected from N, S and O, or which can be substituted by none or more halogen, O, S or —NRpRq, wherein, Rp and Rq independently is hydrogen or C1-C6 alkyl. In this case, A1 is preferably CH2 and the general formula (I) turns into formula (Ib2),
Figure US08969373-20150303-C00011
In formula (Ib2),
  • Ar is a substituted or unsubstituted aryl or heteroaryl, preferably, Ar is a 6 membered aryl or a 5˜6 membered heteroaryl which is substituted optionally by 1 or more RAr; wherein, RAr is selected from the following substituent group: halogen, amino, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 hydroxyalkyl and (C1-C6) alkylamido.
  • A is O, S, CH, NH or NR′, wherein, R′ is C1-C6 alkyl substituted or unsubstituted by halogen which includes 0˜3 heteroatom(s) of O, S or N.
  • Ra, Rb, Rc and Rd independently is H, OH, halogen or —Y1—Rm, Y1 is linking bond, O, S, SO, SO2 or NRn; Rm is hydrogen, or, Rm is an unsubstituted substituent or one substituted by 1˜3 Rm′ which is selected from the following group: (C1-C8) alkyl, N≡C—(C1-C6) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) cycloalkyl, (C3-C7 cycloalkyl) (C1-C6) alkyl, and 5˜6 membered aryl or heteroaryl including 0˜2 heteroatom(s) independently selected from N, O, S; Rn is H, (C1-C6) alkyl or (C3-C6) cycloalkyl. Wherein, Rm′ is a substituent selected from the following group: halogen, (C1-C6) alkyl substituted optionally by (C1-C6)alkyl-O— or (C3-C6)cycloalkyl-O—, (C1-C6) haloalkyl, (C3-C7)cycloalkyl, (C1-C6)alkyl-O—, heteroaryl, —NH2, (C1-C4 alkyl)NH— and (C1-C4 alkyl)2N—.
  • A2 is N, O or linking bond.
  • R1′ is an unsubstituted substituent or one substituted by 1 to more R1″ which is selected from the following group: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, (aryl) C1-C2 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl) C1-C2 alkyl, C3-C7 cycloalkenyl, (C3-C7 cycloalkenyl) C1-C2 alkyl, heterocycloalkyl, (heterocycloalkyl) C1-C2 alkyl, C5-C10 heteroaryl and (C5-C10 heteroaryl) C1-C2 alkyl;
  • R1″ is a substituent selected from the following group: halogen, OH, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, —NH2, (C1-C6 alkyl)-NH— and —N(C1-C6 alkyl)2;
    preferably, R1′ is
Figure US08969373-20150303-C00012
  • R4 is C1-C10 alkoxycarbonyl, (C1-C10 alkyl)-NHCO, (C1-C10 alkyl)2NCO, aryl, heteroaryl or formyl substituted by 3˜7 membered cycloalkyl, heterocycloalkyl or cycloalkoxy, which may be not substituted or substituted by 1 or more R4′; wherein, R4′ is a substituent selected from the following group: halogen, OH, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, —NH2, (C1-C6 alkyl)-NH— and —N(C1-C6 alkyl)2, (C1-C6 alkyl)-SO2—;
    preferably, R4 is
Figure US08969373-20150303-C00013
wherein, Rx and Ry independently is F, Cl, C1-C6 alkyl or C1-C6 alkoxyl, Rz is C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 alkylformyl or (C1-C6 alkyl)-SO2—.
In the present invention,
Figure US08969373-20150303-P00001
means that it can be double bond or single bond either.
In the present invention, the detailed compound is preferably as follows:
Figure US08969373-20150303-C00014
Figure US08969373-20150303-C00015
Figure US08969373-20150303-C00016
Figure US08969373-20150303-C00017
Figure US08969373-20150303-C00018
Figure US08969373-20150303-C00019
Figure US08969373-20150303-C00020
Figure US08969373-20150303-C00021
Figure US08969373-20150303-C00022
Figure US08969373-20150303-C00023
Figure US08969373-20150303-C00024
Figure US08969373-20150303-C00025
Figure US08969373-20150303-C00026
Figure US08969373-20150303-C00027
The second aim of the present invention is to provide a pharmaceutical composition that comprises the compound having the general formula (I) of the present invention and pharmaceutically acceptable carrier(s). Wherein, the pharmaceutical composition of the present invention can also be used in combination with other anti-virus drugs such as interferon or ribavirin.
The third aim of the present invention is to provide a use of the compound of the present invention in preparation of a drug for preventing virus infection or antivirus, wherein, said virus is preferably hepatitis virus, more preferably hepatitis C virus.
The forth aim of the present invention is to provide a method where an effective amount of the compound of the present invention is administered to a patient infected with hepatitis virus, more preferably with HCV.
The synthesis process of the compound having the formula (I) of the present invention is as follows:
Figure US08969373-20150303-C00028
Specifically, when Z3 links with O, the synthesis of intermediate M that used to synthesize the compound having the formula (Ia) is as follows:
Figure US08969373-20150303-C00029
Specifically, when Z1 links with O, the synthesis of intermediate M that used to synthesize the compound having the formula (Ib1) and the formula (Ib2) is as follows:
Figure US08969373-20150303-C00030
DETAILED DESCRIPTION OF THE INVENTION EXAMPLE 1 Intermediate 1 (Abbreviated as M1, Same as Following)
Figure US08969373-20150303-C00031
Step S1A: Synthesis of 1-(3-amino-benzofuran-2-yl)-ethanone (1A)
To a solution of 2-hydroxy-benzonitrile (1000 mmol) in DMF (dimethylformamide, 80 mL) was added K2CO3 (207 g, 1.5 mol) portionwise under stirring, followed by 1-chloro-propan-2-one (139 g, 1.5 mol). After addition, the mixture was heated to 120° C. and stirred at that temperature for 2 hours. TLC showed the reaction was completed. The reaction mixture was cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate, washed with brine, dried and concentrated. The residue was washed with dichloromethane, filtered and dried to give 112 g of 1-(3-amino-benzofuran-2-yl)-ethanone (1A).
1H-NMR (DMSO): δ (ppm): 7.98 (d, J=8.0 Hz, 1H), 7.52 (m, 2H), 7.28 (dt, J=6.4, 1.6 Hz, 1H), 6.95 (brs, 2H), 2.37 (s, 3H). MS (ESI): M++1=176.18.
Step S1B: Synthesis of (E) 2-cinnamoyl-3-amino-benzofuran (1B)
To a solution of 1A (114 mmol) in MeOH (200 mL) was added NaOH (18.2 g, 445 mmol). The reaction was exothermic. After cooled to room temperature, benzaldehyde (14.5 g, 137 mmol) was added. The mixture was stirred overnight under N2. TLC monitored the reaction. After the reaction completed, the reaction mixture was poured into ice-water under stirring. The solids precipitated out and were collected by filtration, and dried to give 1B (26 g).
1H-NMR (DMSO): δ (ppm): 8.03 (d, J=8 Hz, 1H), 7.80 (dd, J1=7.6 Hz, J2=1.6 Hz, 2H), 7.70 (d, J=16 Hz, 1H), 7.55-7.59 (m, 3H), 7.47 (m, 3H), 7.44-7.48 (m, 3H). MS (ESI): M++1=265.3.
Step S1C: Synthesis of 2-phenyl-2,3-dihydrobenzofuron[3,2-b]pyridin-4(1H)-one (1C)
1B (98 mmol) was dissolved in a mixture of AcOH (150 ml) and H3PO4 (150 mL) The reaction mixture was heated to 120° C., and reacted under stirring for 4 hours. TLC monitored the reaction. After the reaction completed, the mixture was cooled and poured into ice-water, filtered and dried to give 1C (21 g).
1H-NMR (DMSO): δ (ppm): 7.98 (s, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.59 (q, J1=10.4 Hz, J2=7.6 Hz,4H), 7.45 (t, J=7.2 Hz, 2H), 7.39 (t, J=7.4 Hz, 1H), 7.32 (m, 1H), 4.98 (dd, J1=14 Hz, J2=4.4 Hz, 1H), 2.86 (dd, J=14, 16.4 Hz, 1H), 2.57 (dd, J=16.4, 4.4 Hz, 1H). MS (ESI): M++1=264.3.
Step S1D: Synthesis of 2-phenyl-4-hydroxyl-benzo[4,5]furo[3,2-b]pyridine (1D)
To a solution of 1C (79.7 mmol) in 1,4-dioxane (100 mL) was added FeCl3.6H2O (110 g, 400 mmol). The mixture was refluxed for 3 hours. TLC showed the reaction completed. The mixture was cooled and poured into cold diluted hydrochloric acid aqueous solution under stirring. The solids were precipitated out and collected by filtration, dried to give 1D (14 g).
1H-NMR (DMSO-d6): δ (ppm): 10.61 (s, 1H), 8.55 (s, 1H), 8.15 (d, J=7.6 Hz, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.55-7.63 (m, 4H), 7.38 (t, J=4.6 Hz, 1H), 7.33 (t, J=3.8 Hz, 1H). MS (ESI): M++1=262.27.
Step S1E: Synthesis of 4-chloro-2-phenyl-benzofuro[3,2-b]pyridine (M1)
1D (53.6 mmol) was added to POCl3 (90 mL), heated to dissolve and stirred at 110° C. for 2.5 hours. TLC showed the reaction completed. POCl3 was evaporated under reduced pressure. The residue was cooled and poured into ice-water under stirring. The solids were collected by filtration and dried to give the desired product M1 (11.5 g).
1H-NMR (DMSO-d6): δ (ppm): 8.29 (s, 1H), 8.22-8.27 (m, 3H), 7.91 (d, J=8.0 Hz, 1H), 7.76 (dt, J=8.2, 1.6 Hz, 1H), 7.49-7.59 (m, 4H). MS (ESI): M++1=280.7.
EXAMPLE 2 Intermediate 2 (M2)
Figure US08969373-20150303-C00032
Step S2A: Synthesis of 2-chloro-6-mercapto-benzonitrile (2A)
The solution of 2,6-dichloro-benzonitrile (20 mmol) in DMSO (dimethyl sulfoxide, 30 mL) was heated to 70° C., followed by addition of Na2S.9H2O portionwise under stirring. The mixture was stirred for 1 hour. TLC monitored the reaction. After the reaction completed, the mixture was cooled and extracted between water and ethyl acetate. The aqueous layer was acidified by hydrochloric acid to pH=3˜4 under stirring. The formed solids were collected by filtration and dried to give 2.3 g of 2-chloro-6-mercapto-benzonitrile (2A). MS (ESI): M++1=170.6.
Step S2B: Synthesis of 1-(3-amino-4-chloro-benzothiophen-2-yl)-ethanone (2B)
The procedure was similar to step S1A, while the starting material was 2-chloro-6-mercapto-benzonitrile (2A) in stead of 2-hydroxy-benzonitrile.
1H-NMR (DMSO-d6): δ (ppm): 7.89 (dd, J=8 Hz, J=0.8 Hz, 1H), 7.84 (b, 2H), 7.53 (t, J=16 Hz, 1H), 7.45 (dd, J1=7.6 Hz, J2=1.2 Hz, 1H), 2.37 (s, 3H). MS (ESI): M++1=226.7.
Step S2C: Synthesis of (E) 2-cinnamoyl-3-amino-4-chloro-benzo[b]thiophene (2C)
The procedure was similar to step S1B, while the starting material was 2B in stead of 1A.
1H-NMR (DMSO-d6): δ (ppm): 8.19 (b, 2H), 7.92 (d, J=8.4 Hz, 1H), 7.79 (m, 2H), 7.70 (d, J=15.6 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.46-7.49 (m, 4H), 7.24 (d, J=15.6 Hz, 1H). MS (ESI): M++1=315.8.
Step S2D: Synthesis of 2-phenyl-9-chloro-2,3-dihydro-benzo[4,5]thieno[3,2-b]pyridin-4(1H)-one (2D)
The procedure was similar to step S1C, while the starting material was 2C in stead of 1B.
MS (ESI): M++1=314.8.
Step S2E: Synthesis of 2-phenyl-9-chloro-4-hydroxyl-benzo[4,5]thieno[3,2-b]pyridine (2E)
The procedure was similar to step S1D, while the starting material was 2D in stead of 1C.
1H-NMR (DMSO): δ (ppm): 11.95 (s, 1H), 8.24 (d, J=8.0 Hz, 2H), 8.12 (dd, J1=7.6 Hz, J2=0.8 Hz, 1H), 7.65 (dd, J=6.4, 1.2 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.49 (t, J=7.2 Hz, 1H). MS (ESI): M++1=312.8.
Step S2F: Synthesis of 4,9-dichloro-2-phenyl-benzo[4,5]thieno[3,2-b]pyridine (M2)
The procedure was similar to step S1E, while the starting material was 2E in stead of 1D.
1H-NMR (DMSO): δ (ppm): 8.43 (s, 1H), 8.40 (dd, J=1.2, 7.6 Hz, 2H), 8.20 (dd, J1=7.6 Hz, J2=1.2 Hz, 1H), 7.73 (dd, J=1.2, 8.0 Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.59 (t, J=7.6 Hz, 2H), 7.53 (dt, J=2.0, 7.6 Hz, 1H). MS (ESI): M++1=331.2.
EXAMPLE 3 Intermediate 3 (M3)
Figure US08969373-20150303-C00033
Step S3A: Synthesis of 2-mercapto-benzonitrile (3A)
The procedure was similar to step S2A, while the starting material was 2-fluoro-benzonitrile in stead of 2,6-dichloro-benzonitrile.
MS (ESI): M++1=136.2.
Step S3B: Synthesis of 1-(3-amino-benzo[b]thiophen-2-yl)-ethanone (3B)
The procedure was similar to step S1A, while the starting material was 2-mercapto-benzonitrile (3A) in stead of 2-hydroxy-benzonitrile.
1H-NMR (DMSO-d6): δ (ppm): 8.19 (d, J=8.4 Hz, 2H), 7.86 (t, J=7.0 Hz, 3H), 7.55 (t, J=7.2 Hz, 1H), 7.43 (t, J=7.2 Hz, 1H), 2.35 (s, 3H). MS (ESI): M++1=193.2.
Step S3C: Synthesis of (E)-2-cinnamoyl 3-amino-benzo[b]thiophene (3C)
The procedure was similar to step S1B, while the starting material was 3B in stead of 1A.
1H-NMR (DMSO-d6): δ (ppm): 8.25 (m, 3H), 7.91 (d, J=8.4 Hz, 1H), 7.79 (d, J=15.6 Hz, 2H), 7.69 (d, J=7.2 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.46 (t, J=6.4 Hz, 4H), 7.23 (d, J=15.6 Hz, 1H). MS (ESI): M++1=280.3.
Step S3D: Synthesis of 2-phenyl-2,3-dihydro-benzo[4,5]thieno[3,2-b]pyridin-4(1H)-one (3D)
The procedure was similar to step S1C, while the starting material was 2C in stead of 1B.
MS (ESI): M++1=280.3.
Step S3E: Synthesis of 2-phenyl-4-hydroxyl-benzothieno[3,2-b]pyridine (3E)
The procedure was similar to step S1D, while the starting material was 3D in stead of 1C.
MS (ESI): M++1=278.3.
Step S3F: Synthesis of 4-chloro-2-phenyl-benzothieno[3,2-b]pyridine (M3)
The procedure was similar to step S1E, while the starting material was 3E in stead of 1D.
1H-NMR (DMSO-d6): δ (ppm): 8.54 (d, J=7.6 Hz, 1H), 8.35 (s, 1H), 8.34 (dd, J=1.6, 7.6 Hz, 1H), 8.20 (d, J=7.6 Hz, 1H), 7.74 (dt, J=7.2, 1.2 Hz, 1H), 7.68 (dt, J=7.6, 1.6 Hz, 1H), 7.51-7.60 (m, 3H). MS (ESI): M++1=296.8.
EXAMPLE 4 Intermediate 4 (M4)
Figure US08969373-20150303-C00034
Step S4A: Synthesis of 2-hydroxy-5-methoxy-benzaldehyde (4A)
To a mixture of MgCl2 (3.48 g, 37.0 mmol), TEA (12.8 mL, 92.1 mmol) and paraformaldehyde (5 g, 167 mmol) in MeCN (100 mL) was added 4-methoxy-phenol (3 g, 24.2 mmol). The mixture was refluxed for 8 hours, cooled to room temperature, then poured into 5% HCl (300 mL), extracted with ethyl acetate (200 mL×3). The combined organic layer was dried, concentrated and purified by column chromatography on silica gel (ethyl acetate/n-hexane=1/5) to give 2.3 g of 2-hydroxy-5-methoxy-benzaldehyde (4A).
1H-NMR (DMSO-d6): δ (ppm): 10.67 (s, 1H), 9.87 (s, 1H), 7.18 (dd, J1=8.8 Hz, J2=3.6 Hz, 1H), 7.02 (d, J=2.8 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 3.83 (s, 3H). MS (ESI): M++1=153.15.
Step S4B: Synthesis of 2-hydroxy-5-methoxy-benzonitrile (4B)
To a solution of 2-hydroxy-5-methoxy-benzaldehyde (10 g, 65.7 mmol) in 95% EtOH (30 mL) was added a solution of hydroxylamine hydrochloride (2.8 g, 78.8 mmol) in water (6 mL), followed a solution of NaOH (4 g, 98.8 mmol) in water. The mixture was stirred at room temperature for 2.5 hours, then extracted with ethyl acetate, dried over anhydrous Na2SO4 and concentrated to give 12 g of solid. To the solid was added Ac2O (15 g, 146.9 mmol) and the mixture was refluxed for 20 min. TLC monitored the reaction. After the reaction completed, the mixture was poured into crash ice. Solids were precipitated out while stirring, which was collected by filtration and dried to give 9 g of 2-hydroxy-5-methoxy-benzonitrile (4B).
MS (ESI): M++1=150.15.
Step S4C: Synthesis of 1-(3-amino-5-methoxy-benzofuran-2-yl)-ethanone (4C)
The procedure was similar to step S1A, while the starting material was 2-hydroxy-5-methoxy-benzonitrile (4B) in stead of 2-hydroxy-benzonitrile.
1H-NMR (DMSO-d6): δ (ppm): 7.52 (d, J=2.4 Hz, 1H), 7.41 (d, J=9.2 Hz, 1H), 7.13 (dd, J=2.8, 9.2 Hz, 1H), 6.82 (s, 2H), 3.79 (s, 3H), 2.34 (s, 3H). MS (ESI): M++1=208.23.
Step S4D: Synthesis of (E)-2-cinnamoyl-3-amino-5-methoxy-benzofuran (4D)
The procedure was similar to step S1B, while the starting material was 4C in stead of 1A.
MS (ESI): M++1=294.32.
Step S4E: Synthesis of 2-phenyl-8-methoxy-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (4E)
The procedure was similar to step S1C, while the starting material was 4D in stead of 1B.
MS (ESI): M++1=294.32.
Step S4F: Synthesis of 2-phenyl-4-hydroxyl-8-methoxy-benzofuro[3,2-b]pyridine (4F)
The procedure was similar to step S1D, while the starting material was 4E in stead of 1C.
MS (ESI): M++1=292.3.
Step S4G: Synthesis of 4-chloro-8-methoxy-2-phenyl-benzofuro[3,2-b]pyridine (M4)
The procedure was similar to step S1E, while the starting material was 4F in stead of 1D.
1H-NMR (DMSO-d6): δ (ppm): 8.29 (s, 1H), 8.26 (dd, J1=6.8 Hz, J2=1.6 Hz, 2H), 7.83 (d, J=8.8 Hz, 1H), 7.70 (d, J=2.8 Hz, 1H), 7.55 (t, J=6.4 Hz, 2H), 7.51 (t, J=7.2 Hz, 1H), 7.31 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H), 3.93 (s, 1H). MS (ESI): M++1=310.75.
EXAMPLE 5 Intermediate 5 (M5)
Figure US08969373-20150303-C00035
Step S5A: Synthesis of 5-chloro-2-hydroxy-benzonitrile (5A)
To a solution of 2-hydroxy-benzonitrile (5 g, 42 mmol) in chloroform (50 mL) was added 15 mL of a solution of NCS(N-chlorosuccinimide, 5.558 g, 44.1 mmol) in chloroform. The reaction mixture was refluxed overnight. TLC monitored the reaction. After the reaction completed, the mixture was poured into ice-water. The organic layer was washed with water, then stayed overnight.
The precipitated solids were collected by filtration. The filtrate was concentrated, recrystallized from chloroform and filtered to give a solid. The two batches of product were combined to give 4 g of 5-chloro-2-hydroxy-benzonitrile (5A).
1H-NMR (DMSO-d6): δ (ppm): 11.44 (s, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.55 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.02 (d, J=9.2 Hz, 1H). MS (ESI): M++1=154.6.
Step S5B: Synthesis of 1-(3-amino-5-chloro-benzofuran-2-yl)-ethanone (5B)
The procedure was similar to step S1A, while the starting material was 5-chloro-2-hydroxy-benzonitrile (5A) in stead of 2-hydroxy-benzonitrile.
1H-NMR (DMSO-d6): δ (ppm): 8.09 (q, 1H), 7.55 (t, J=1.2 Hz, 2H), 6.92 (b, 2H), 2.37 (s, 3H). MS (ESI): M++1=212.6.
Step S5C: Synthesis of (E)-2-cinnamoyl-3-amino-5-chloro-benzofuran (5C)
The procedure was similar to step S1B, while the starting material was 5B in stead of 1A.
1H-NMR (DMSO-d6): δ (ppm): 8.14 (m, 1H), 7.78-7.81 (m, 2H), 7.70 (d, J=15.6 Hz, 1H), 7.60 (m, 2H), 7.50 (d, J=15.6 Hz, 1H), 7.45-7.49 (m, 3H), 7.24 (b, 2H). MS (ESI): M++1=298.7.
Step S5D: Synthesis of 2-phenyl-8-chloro-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (5D)
The procedure was similar to step S1C, while the starting material was 5C in stead of 1B.
MS (ESI): M++1=298.7.
Step S5E: Synthesis of 2-phenyl-8-chloro-4-hydroxyl-benzofuro[3,2-b]pyridine (5E)
The procedure was similar to step S1D, while the starting material was 5D in stead of 1C.
MS (ESI): M++1=296.7.
Step S5F: Synthesis of 4,8-dichloro-2-phenyl-benzo[4,5]furo[3,2-b]pyridine (M5)
The procedure was similar to step S1E, while the starting material was 5E in stead of 1D.
1H-NMR (DMSO-d6): δ (ppm): 8.37 (s, 1H), 8.30 (d, J=2.4 Hz, 1H), 8.25 (dd, J1=8.4 Hz, J2=1.6 Hz, 2H), 7.96 (d, J=8.8 Hz, 1H), 7.78 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.55 (dt, J=7.6, 1.6 Hz, 2H), 7.52 (t, J=7.6 Hz, 1H). MS (ESI): M++1=315.2.
EXAMPLE 6 Intermediate 6 (M6)
Figure US08969373-20150303-C00036
Step S6A: Synthesis of 1-(3-amino-5-bromo-benzofuran-2-yl)-ethanone (6A)
A mixture of 5-bromo-2-hydroxy-benzonitrile (15.06 g, 76.06 mmol), 1-chloro-propan-2-one (10.56 g, 114.09 mmol, 1.5 eq) and K2CO3 (15.77 g, 114.09 mmol, 1.5 eq) was added to DMF (100 mL) The mixture was stirred at 90° C. for 2 hours. TLC monitored the reaction. After the reaction completed, the mixture was cooled to room temperature and poured into water (500 mL).
The yellow solids precipitated out were collected by filtration to give 1-(3-amino-5-bromo-benzofuran-2-yl)-ethanone (6A) (19.2 g, 99.36% yield).
1H-NMR (400 MHz, DMSO-d6): δ (ppm): 8.24 (d, J=2.0 Hz, 1H), 7.64-7.67 (dd, J1=8.8 Hz, J2=2.0 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 6.91 (s, 2H), 2.37 (s, 3H).
Step S6B: Synthesis of (Z)-2-cinnamoyl-3-amino-5-bromo-benzofuran (6B)
A mixture of 1-(3-amino-5-bromo-benzofuran-2-yl)-ethanone (19.2 g, 75.57 mmol), NaOH (12.09 g, 302.27 mmol, 4 eq) and benzaldehyde (10.42 g, 98.24 mmol, 1.3 eq) was added to MeOH (400 mL) The mixture was stirred at 45° C. for 48 hours. TLC monitored the reaction. After the reaction completed, the mixture was cooled to room temperature and poured into water (400 mL).
The yellow solids precipitated out were collected by filtration to give (Z)-2-cinnamoyl-3-amino-5-bromo-benzofuran (6B) (28 g, 100% yield).
1H-NMR (400 MHz, DMSO-d6) δ 8.29 (d, J=1.6 Hz, 1H), 7.78-7.80 (m, 2H), 7.68-7.72 (m, 2H), 7.57 (s, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.45-7.48 (m, 3H), 7.24 (s, 2H).
Step S6C: Synthesis of 8-bromo-2-phenyl-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (6C)
A solution of (Z)-2-cinnamoyl-3-amino-5-bromo-benzofuran (28 g, 81.83 mmol) in AcOH (70 mL) and H3PO4 (70 mL) was refluxed for 2 hours. TLC showed the reaction completed. The mixture was cooled to room temperature and poured into water (250 mL) The yellow solids precipitated out were collected by filtration to give 8-bromo-2-phenyl-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (6C) (23.8 g, 85% yield).
1H-NMR (400 MHz, DMSO-d6) δ 8.2 (d, J=1.6 Hz, 1H), 7.94 (s, 1H), 7.70-7.73 (dd, J1=9.2 Hz, J2=2.8 Hz, 1H), 7.56-7.59 (m, 3H), 7.44 (t, J=7.2 Hz, 3H), 7.37-7.40 (m, 1H), 4.97 (dd, J1=14.6 Hz, J2=4.8 Hz, 1H), 2.87 (dd, J1=16.4 Hz, J2=14.0 Hz, 1H), 2.54-2.60 (dd, J1=16.0 Hz, J2=4.4 Hz, 1H).
Step S6D: Synthesis of 4-hydroxyl-8-bromo-2-phenyl-benzofuro[3,2-b]pyridine (6D)
A mixture of 8-bromo-2-phenyl-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (23.8 g, 69.55 mmol) and FeCl3.6H2O (112.78 g, 417.3 mmol) was added to 1,4-dioxane (300 mL) The mixture was refluxed for 16 hours. TLC showed the reaction completed. The mixture was cooled to room temperature and poured into ice-water (500 mL) The yellow solids precipitated out were collected by filtration to give 4-hydroxyl-8-bromo-2-phenyl-benzofuro[3,2-b]pyridine (6D) (15.7 g, 66.36% yield).
Step S6E: Synthesis of 8-bromo-4-chloro-2-phenyl-benzofuro[3,2-b]pyridine (M6)
4-hydroxyl-8-bromo-2-phenyl-benzofuro[3,2-b]pyridine (8.7 g, 25.72 mmol) was added to POCl3 (100 mL) The mixture was refluxed for 4 hours. TLC showed the reaction completed. POCl3 was evaporated under reduced pressure. The residue was poured into ice-water under stirring. The yellow solids precipitated out were collected by filtration to give 8-bromo-4-chloro-2-phenyl-benzofuro[3,2-b]pyridine (M6) (6.52 g, 71.01% yield).
1H-NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 8.09 (d, J=7.2 Hz, 2H), 7.87 (s, 1H), 7.70-7.74 (dd, J1=8.8 Hz, J2=2.0 Hz, 1H), 7.53-7.59 (m, 3H), 7.47-7.51 (m, 1H).
EXAMPLE 7 Synthesis of 7G
Figure US08969373-20150303-C00037
Step S7A: Synthesis of 2-chloro-3,6-dihydroxy-benzaldehyde (7A)
2,5-dihydroxy-benzaldehyde (100 g, 0.725 mol) was dissolved in MeCN (1L). To the solution was added NCS(N-chlorosuccinimide, 106 g, 1.1 eq) in batches under N2 protection. After addition completed, the mixture was stirred at room temperature overnight. TLC monitored the reaction. After the reaction completed, NaHSO3(38%, 500 mL) was added to the mixture, then extracted with ethyl acetate (3×600 mL) The organic layer was washed with water (2×600 mL) and brine (600 mL), dried over anhydrous MgSO4, concentrated to give a crude product, which was recrystallized to give the desired product 7A (25.6 g, 20.5% yield), as a yellow solid.
1H-NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 10.34 (s, 1H), 9.94 (s, 1H), 7.23 (d, J=9.2 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H).
Step S7B: Synthesis of (E)-2-chloro-3,6-dihydroxy-benzaldehyde oxime (7B)
A mixture of 7A (25.0 g, 144.87 mmol), hydroxylamine hydrochloride (12.08 g, 173.84 mmol, 1.2 eq) and NaOH (8.69 g, 217.3 mmol, 1.5 eq) in EtOH (200 mL) and H2O (100 mL) was stirred at room temperature overnight. TLC monitored the reaction. After the reaction completed, the mixture was extracted with ethyl acetate and concentrated to give a yellow solid 7B (34.2 g, 100% yield).
Step S7C: Synthesis of 2-chloro-3-cyano-1,4-diacetoxy-benzene (7C)
7B (34.2 g, 182.32 mmol) was dissolved in Ac2O (200 mL) The reaction mixture was refluxed for 24 hours under stirring. TLC monitored the reaction. After the reaction completed, the mixture was cooled to room temperature and poured into water (250 mL), extracted with ethyl acetate, concentrated and purified by column chromatography on silica gel to give product 7C (17.3 g, 37.2% yield).
Step S7D: Synthesis of acetic acid 2-chloro-3-cyano-4-hydroxy-phenyl ester (7D)
7C (13.8 g, 54.4 mmol) was dissolved in MeOH (80 ml) and dichloromethane (80 mL). To the solution was added K2CO3 (7.52 g, 54.4 mmol, 1 eq). The reaction mixture was stirred at room temperature for 40 min. TLC monitored the reaction. After the reaction completed, the mixture was acidified by 1N hydrochloric acid to pH˜6, extracted with dichloromethane and concentrated to give white solid 7D (7.8 g, 67.76% yield).
1H-NMR (400 MHz, CDCl3) δ 11.76 (s, 1H), 7.46 (d, J=9.2 Hz, 1H), 7.03 (d, J=9.2 Hz, 1H), 2.32 (s, 3H).
Step S7E: Synthesis of 2-acetyl-3-amino-4-chloro-5-acetoxyl-benzofuran (7E)
To a solution of 7D (2.2 g, 10.4 mmol) in MeCN (20 mL) was added 1-chloro-propan-2-one (1.25 g, 13.52 mmol, 1.3 eq), followed by K2CO3 (1.868 g, 13.52 mmol, 1.3 eq). The mixture was stirred at 90° C. for 40 min. TLC monitored the reaction. After the reaction completed, the mixture was quenched with water (100 mL) The white solids were precipitated out and collected by filtration and dried to give product 7E (3 g, 100% yield).
Step S7F: Synthesis of 2-acetyl-3-amino-4-chloro-5-hydroxy-benzofuran (7F)
To a solution of 7E (12.8 g, 47.82 mmol) in MeOH (100 mL) was added a solution of saturated aqueous of K2CO3 (6.61 g, 47.82 mmol, 1 eq.) dropwise. The mixture was stirred at room temperature overnight. TLC monitored the reaction. After the reaction completed, the mixture was acidified by 1N hydrochloric acid to pH˜6, extracted with ethyl acetate and concentrated to give white solid 7F (10.2 g, 94.54% yield).
1H-NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.46 (s, 2H), 2.37 (s, 3H).
Step S7G: Synthesis of 2-acetyl-3-amino-4-chloro-5-methoxyl-benzofuran (7G)
To a solution of 7F (0.5 g, 2.22 mmol) in DMF (5 mL) was added anhydrous CsF (1.01 g, 6.65 mmol, 3 eq), followed by MeI (0.377 g, 2.66 mmol, 1.2 eq) dropwise. The mixture was stirred at room temperature for 40 min. TLC monitored the reaction. After the reaction completed, the mixture was poured into water (25 mL) The white solids were precipitated out, collected by filtration and purified to give product 7G (0.33 g, 62.14% yield).
1H-NMR (400 MHz, CDCl3) δ 7.50 (d, J=9.2 Hz, 1H), 7.42 (d, J=9.2 Hz, 1H), 6.51 (s, 2H), 3.89 (s, 3H), 2.38 (s, 3H).
EXAMPLE 8 Intermediate 8 (M8)
Figure US08969373-20150303-C00038
Step S8A: Synthesis of 2-cinnamoyl-3-amino-4-chloro-5-methoxy-benzofuran (8A)
A mixture of 7G (1.5 g, 6.26 mmol), benzaldehyde (0.863 g, 8.14 mmol, 1.3 eq) and NaOH (1.0 g, 25.04 mmol, 4 eq) in MeOH (20 mL) was stirred at 45° C. for 24 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (20 mL) The yellow solids precipitated out were collected by filtration and dried to give product 8A (1.9 g, 92.6% yield).
Step S8B: Synthesis of 9-chloro-8-methoxy-2-phenyl-2,3-dihydrobenzofuro[3,2-b]pyridin-4(1H)-one (8B)
A mixture of 8A (1.9 g, 5.8 mmol) in AcOH (10 mL) and H3PO4 (10 mL) was refluxed for 2 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (20 mL) The yellow solids were precipitated out, collected by filtration and dried to give product 8B (1.78 g, 93.68% yield).
Step S8C: Synthesis of 4-hydroxyl-9-chloro-8-methoxy-2-phenyl-benzofuro[3,2-b]pyridine (8C)
A mixture of 8B (1.78 g, 5.43 mmol) and FeCl3.6H2O (6.57 g, 32.58 mmol, 6 eq) was added to 1,4-dioxane (40 mL) The mixture was refluxed for 16 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (50 mL) The brown solids were precipitated out, collected by filtration and dried to give product 8C (1.5 g, 84.8% yield).
Step S8D: Synthesis of 4,9-dichloro-8-methoxy-2-phenyl-benzofuro[3,2-b]pyridine (M8)
A mixture of 8C (1.4 g, 4.3 mmol) in POCl3 (20 mL) was refluxed for 2 hours. TLC monitored the reaction. After the reaction completed, POCl3 was evaporated under reduced pressure. The residue was poured into ice-water. The yellow solids were precipitated out, collected by filtration and purified by column chromatography to give product M8 (1.22 g, 82.5% yield).
1H-NMR (400 MHz, CDCl3) δ 8.16 (d, J=7.2 Hz, 2H), 7.88 (s, 1H), 7.44-7.55 (m, 4H), 7.19-7.22 (d, J=8.8 Hz, 1H), 4.02(s, 3H).
EXAMPLE 9 Intermediate 9 (M9)
Figure US08969373-20150303-C00039
Step S9A: Synthesis of (E)-1-(3-amino-4-chloro-5-methoxy-benzofuran-2-yl)-3-(2-isopropyl-thiazol-5-yl)-2-propen-1-one (9A)
7G (3 g, 12.5 mmol) was dissolved in THF (tetrahydrofuran, 30 mL). To the solution was added 2-isopropyl-thiazole-5-carbaldehyde (2.33 g, 15 mmol, 1.2 eq), followed by crushed NaOH powder (1 g, 25 mmol, 2 eq). The reaction mixture was stirred at room temperature for 10 min. The solution became dark and some solids formed. The mixture was poured into ice-water under stirring.
The solids were collected by filtration, dried and purified by column chromatography on silica gel to give 3.5 g of pure product (9A).
1H-NMR (400 MHz, CDCl3) δ 7.88 (d, J=16.0 Hz, 1H), 7.86 (s, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.21 (d, J=16.0 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.38 (s, 2H), 3.97 (s, 3H), 3.35 (m, 1H), 1.44 (d, J=7.2 Hz, 6H); ES-LCMS m/z N/A.
Step S9B: Synthesis of 9-chloro-2-(2-isopropylthiazol-5-yl)-8-methoxy-1,2-dihydro-benzofuro[3,2-b]pyridin-4-one (9B)
9A (3.5 g, 9.28 mmol) was added to MeCN (50 mL) and stirred at room temperature. To the mixture was added ZnCl2 (1.91 g, 13.93 mmol, 1.5 eq), followed by AcOH (50 mL) and H3PO4 (50 mL) The reaction mixture was heated to 80° C. and stirred overnight. After reaction completed, the mixture was cooled and poured into crushed ice under stirring, neutralized to pH=7˜8, extracted with ethyl acetate, dried and concentrated to give 2.4 g of product (9B).
1H-NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 5.56 (brs, 1H), 5.25 (dd, J=12.0, 4.8 Hz, 1H), 3.97 (s, 3H), 3.25-3.35 (m, 1H), 2.29-3.02 (m, 2H), 1.45 (d, J=7.0 Hz, 6H).
Step S9C: Synthesis of 4-hydroxyl-9-chloro-2-(2-isopropyl-thiazol-5-yl)-8-methoxy-benzofuro[3,2-b]pyridine (9C)
The crude 9B (2.4 g, 6.9 mmol) was dissolved in THF (50 mL). To the solution was added activated MnO2 (3.6 g, 40.4 mmol, 6 eq). The mixture was refluxed overnight. After reaction completed, the reaction mixture was cooled and filtered. The cake was washed well with THF and MeOH. The filtrate was concentrated and purified by column chromatography on silica gel to give 300 mg of pure product (9C).
1H-NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.48 (s, 1H), 7.46 (d, J=8.8 Hz, 1H), 3.96 (s, 3H), 3.30 (m, 1H), 1.385 (d, J=7.3 Hz, 6H).
Step S9D: Synthesis of 4,9-dichloro-2-(2-isopropyl-thiazol-5-yl)-8-methoxy-benzofuro[3,2-b]pyridine (M9)
A mixture of 9C (300 mg, 0.80 mmol) in POCl3 (5 mL) was refluxed for 30 min. After reaction completed, POCl3 was evaporated under reduced pressure. The residue was poured into crushed ice under stirring for 10 min. The solids were collected by filtration and dried to give 320 mg of crude product, which was dissolved in dichloromethane, purified by flash chromatography and concentrated to give 175 mg of pure product (M9).
1H-NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.79 (s, 1H), 7.567 (d, J=8.8 Hz, 1H), 7.268 (d, J=8.8 Hz, 1H), 4.04 (s, 3H), 3.39 (m, 1H), 1.50 (d, J=7.2 Hz, 6H); ES-LCMS m/z N/A.
EXAMPLE 10 Intermediate 10 (M10)
Figure US08969373-20150303-C00040
Step S10A: Synthesis of 1-(3-amino-4-chloro-5-methoxy-benzofuran-2-yl)-3-(2-isopropyl-thiazol-4-yl)-2-propen-1-one (10A)
A mixture of 7G (6.4 g, 26.7 mmol), 2-isopropyl-thiazole-4-carbaldehyde (4.8 g, 30.92 mmol, 1.16 eq) and NaOH (4.27 g, 106.8 mmol, 4 eq) in MeOH (200 mL) was stirred at 45° C. for 24 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (200 mL) The yellow precipitates were collected by filtration and dried to give product 10A (9.96 g, 98.9% yield).
1H-NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.63 (s, 1H), 7.60 (d, J=9.2 Hz, 1H), 7.45-7.48 (d, J=9.2 Hz, 1H), 6.86 (s, 2H), 3.91 (s, 3H), 3.39 (m, 1H), 1.38 (d, J=6.4 Hz, 6H).
Step S10B: Synthesis of 9-chloro-2-(2-isopropyl-thiazol-4-yl)-8-methoxy-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (10B)
10A (9.96 g, 26.43 mmol) was dissolved in AcOH (50 mL) and H3PO4 (50 mL). The solution was refluxed for 2 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (200 mL) The brown precipitates were collected by filtration and dried to give product 10B (10.8 g), which was used for the next step directly.
Step S10C: Synthesis of 4-hydroxyl-9-chloro-2-(2-isopropyl-thiazol-4-yl)-8-methoxy-benzofuro[3,2-b]pyridine (10C)
A mixture of 10B (10.3 g, 27.33 mmol, crude) and FeCl3.6H2O (33.04 g, 164.0 mmol, 6 eq) was added to 1,4-dioxane (300 mL) The mixture was refluxed for 16 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (300 mL), extracted with ethyl acetate and concentrated to give a crude product 10C (8.75 g), which was used for the next step directly.
Step S10D: Synthesis of 4,9-dichloro-2-(2-isopropyl-thiazol-4-yl)-8-methoxy-benzofuro[3,2-b]pyridine (M10)
The crude 10C (8.75 g, 23.34 mmol) was added to POCl3 (200 mL) The mixture was refluxed for 2 hours. TLC monitored the reaction. After the reaction completed, POCl3 was evaporated under reduced pressure. The residue was poured into crushed ice under stirring. The yellow solids were collected by filtration and purified by flash chromatography to give product M10 (0.66 g).
1H-NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 8.17 (s, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 4.03 (s, 3H), 3.42 (m, 1H), 1.50 (d, J=6.0 Hz, 6H).
EXAMPLE 11 Intermediate 11 (M11)
Figure US08969373-20150303-C00041
Figure US08969373-20150303-C00042
Step S11A: Synthesis of isobutyryl-thiourea (11A)
Thiourea (152 g, 2 mol) was dissolved in toluene (1520 mL). To the solution was added isobutyryl chloride (213 g, 2 mol) under mechanical stirring. The reaction mixture was refluxed for 3 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The filtrate was concentrated to dryness. The yellow solids were collected by filtration, washed with petroleum ether (100 mL×3) to appear white, dried in vacumm to give the desired product 11A (90 g, 30% yield) as a white solid (mp: 114˜116° C.).
1H-NMR (CDCl3): δ 1.24 (d, J=6.0 Hz, 2×3H), δ 2.68 (m, J=6.93 Hz, 1H).
Step S11B: Synthesis of 2-isobutyrylamino-thiazole-4-carboxylic acid ethyl ester (11B)
11A (29.6 g, 0.2 mol) was dissolved in anhydrous EtOH (300 mL). To the solution was added 3-bromo-2-oxo-propionic acid (34 g, 0.17 mol). The mixture was refluxed for 2 hours, then cooled to room temperature, concentrated to dryness, dissolved with ethyl acetate, washed with saturated aqueous of NaHCO3. The organic layer was dried and concentrated to give a crude product 11B (48 g, 100% yield).
1H-NMR (CDCl3): δ 1.356-1.373 (d, J=6.8 Hz, 2×3H), δ 2.828-2.845 (m, J=6.93 Hz, 1H), δ 8.094 (s, 1H), δ 10.026 (s, 1H), δ 11.605 (b, 1H).
Step S11C: Synthesis of 2-isobutyrylamino-thiazole-4-methanol (11C)
11B (0.73 g, 3 mmol) was dissolved in THF (14 mL). To the solution was added LiBH4 (0.23 g, 10 mmol) in batches at room temperature. The reaction mixture was refluxed overnight, then quenched with 14 mL of anhydrous MeOH and concentrated to dryness. The residue was dissolved in dichloromethane and filtered. The filtrate was concentrated and dried to give a crude product 11C (0.48 g, 100% yield).
1H-NMR (CDCl3): δ 1.32 (d, J=5.0 Hz, 2×3H), δ 2.58-2.73 (m, 1H), δ 4.68 (s, 2H), δ 6.82 (s, 1H).
Step S11D: Synthesis of N-(4-formyl-thiazol-2-yl)-isobutyramide (11D)
11C (0.5 g, 2.5 mmol) was dissolved in THF (10 mL). To the solution at room temperature was added activated MnO2 (1.74 g, 20 mmol). The reaction mixture was refluxed overnight, then filtered. The filtrate was concentrated and dried to give a crude product 11D (0.25 g, 50% yield).
1H-NMR (CDCl3): δ 1.32 (d, J=6.8 Hz, 6H), δ 2.58-2.73 (m, 1H), δ 7.88 (s, 1H), δ 9.88 (s, 1H), δ 10.24 (brs, 1H).
Step S11E: Synthesis of N-{4-[3-(3-amino-4-chloro-5-methoxy-benzofuran-2-yl)-3-oxo-propenyl]-thiazol-2-yl}-isobutyramide (11E)
7G (2.5 g, 10.4 mmol) was dissolved in THF (25 mL). To the solution was added 11D (2.4 g, 1.2 eq, 12.5 mmol), followed by crushed NaOH powder (0.8 g, 2 eq, 20.8 mmol). The reaction mixture was stirred at room temperature for about 1 hour and the solution was getting darker. After reaction completed, the mixture was poured into ice-water under stirring. The solids were collected by filtration, dried and purified by column chromatography on silica gel to give 2.6 g of pure product 11E.
1H-NMR (400 MHz, d-CDCl3) δ 11.48 (brs, 1H), 7.64 (m, 2H), 7.26 (d, J=8.8 Hz, 1H), 7.23 (s, 1H), 7.18 (d, J=8.8 Hz, 1H), 6.41 (s, 2H), 3.96 (s, 3H), 2.78 (m, 1H), 1.31 (d, J=7.2 Hz, 6H).
Step S11F: Synthesis of 9-chloro-2-(2-isobutyrylamino-thiazole-4-yl)-8-methoxy-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (11F)
To a mixture of 11E (2.6 g, 6.19 mmol) in MeCN (30 mL) was added ZnCl2 (1.27 g, 1.5 eq, 9.3 mmol) at room temperature, followed by AcOH (30 mL) and H3PO4 (30 mL) The reaction mixture was stirred 80° C. overnight. After reaction completed, the mixture was cooled and poured into crushed ice under stirring, neutralized to pH=7˜8, extracted with ethyl acetate, dried and concentrated to give 1.6 g of crude product, which was purified by column chromatography on silica gel to give 500 mg of pure product (11F).
1H-NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.134 (brs, 1H), 6.99 (s, 1H), 4.97 (m, 1H), 3.91 (s, 3H), 2.91 (m, 2H), 2.73 (m, 1H), 1.10 (d, J=7.2 Hz, 6H).
Step S11G: Synthesis of 4-hydroxyl-9-chloro-2-(2-isobutyrylamino-thiazole-4-yl)-8-methoxy-benzofuro[3,2-b]pyridine (11G)
11F (500 mg, 1.19 mmol) was dissolved in THF (tetrahydrofuran, 30 mL). To the solution was added activated MnO2 (600 mg, 6 eq, 6.9 mmol). The mixture was refluxed for 48 hours. After reaction completed, the mixture was cooled and filtered. The cake was washed well with THF and MeOH. The filtrate was concentrated and purified by column chromatography on silica gel to give 300 mg of pure product (11G).
1H-NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 7.82 (s, 1H), 7.74 (d, J=9.6 Hz, 1H), 7.66 (s, 1H), 7.46 (d, J=9.6 Hz, 1H), 3.97 (s, 3H), 2.81 (m, 1H), 1.16 (d, J=7.2 Hz, 6H).
Step S11H: Synthesis of 4,9-dichloro-2-(2-isobutyrylamino-thiazole-4-yl)-8-methoxy-2,3-dihydro-benzofuro[3,2-b]pyridine (M11)
A mixture of 11G (300 mg, 0.72 mmol) in POCl3 (5 mL) was refluxed for 30 min. After reaction completed, POCl3 was evaporated under reduced pressure. The residue was poured into crushed ice and stirred for 10 min. The solids were collected by filtration and dried to give 161 mg of product (M11).
1H-NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.97 (s, 1H), 7.601 (d, J=8.8 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 4.06 (s, 3H), 2.99 (m, 1H), 1.3 (d, J=7.2 Hz, 6H).
EXAMPLE 12 Synthesis of 12G
Figure US08969373-20150303-C00043
Step S12A: Synthesis of 2-bromo-3,6-dihydroxy-benzaldehyde (12A)
2,5-dihydroxy-benzaldehyde (100 g, 0.72 mol) was dissolved in chlorform (1L).
To the solution was added Na3PO4 (77 g), followed by Br2 (150 g, 0.94 mol) dropwise at room temperature. The mixture was stirred for 2.5 hours. To the reaction mixture was added aq.NH4Cl. The precipitated solid was collected by filtration, then dissolved in ethyl acetate, washed with water. The organic layer was dried over anhydrous Na2SO4, concentrated and purified by column chromatography on silica gel to give product 12A (90 g, 57.2% yield).
Step S12B: Synthesis of 2-bromo-3,6-dihydroxy-benzaldehyde oxime (12B)
To a mixture of 2-bromo-3,6-dihydroxy-benzaldehyde (12A) (50 g, 0.23 mol) and hydroxylamine hydrochloride (19.2 g, 0.28 mol) was added 95% EtOH (500 mL), followed by NaOH (13.8 g, 0.345 mol). The reaction mixture was stirred at room temperature for 2 hours, then extracted with ethyl acetate and concentrated to give 2-bromo-3,6-dihydroxy-benzaldehyde oxime (12B) (45 g, 84.1% yield) as a solid.
Step S12C: Synthesis of 2-bromo-3-cyano-1,4-diacetoxylbenzene (12C)
A mixture of 12B (45 g, 0.193 mol) and sodium acetate (3 g) in Ac2O (200 mL) was heated to reflux overnight. The reaction mixture was evaporated under reduced pressure to remove Ac2O. The residue was poured into water and stirred for 1 hour. The precipitated solids were collected by filtration and dried to give 12C (40 g, 69.1% yield).
1H-NMR (400 MHz, DMSO-d6) δ 7.79 (d, J=9.2 Hz, 1H), 7.61 (d, J=9.2 Hz, 1H), 2.40 (s, 3H), 2.38 (s, 3H).
Step S12D: Synthesis of 2-bromo-3-cyano-4-hydroxy-phenyl acetate (12D)
12C (15 g, 0.05 mol) was added to MeOH (52 ml) and dichloromethane (52 mL). To the mixture was added K2CO3 (7 g, 0.05 mol) in batches at room temperature. The reaction mixture was stirred overnight at room temperture, then neutralized with diluted hydrochloric acid to pH=6˜7, extracted with dichloromethane, dried over anhydrous Na2SO4 and concentrated to give 12D (8 g, 62.1% yield).
1H-NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.44 (d, J=9.2 Hz, 1H), 7.06 (d, J=9.2 Hz, 1H), 2.31 (s, 3H).
Step S12E: Synthesis of 2-acetyl-3-amino-4-bromo-5-acetoxyl-benzofuran (12E)
To a mixture of 12D (7 g, 0.027 mol) and 1-chloro-propan-2-one (3 mL) in DMF (30 mL) was added K2CO3 (4.1 g, 0.029 mol). The reaction mixture was stirred at 90° C. for 1 hour. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and added dropwise to ice-water. The precipitated solids were collected by filtration to give a crude product 12E (6.8 g, 79.6% yield).
1H-NMR (400 MHz, DMSO-d6) δ 7.65 (d, J=9.2 Hz, 1H), 7.48 (d, J=9.2 Hz, 1H), 6.49 (s, 2H), 2.41 (s, 3H), 2.36 (s, 3H).
Step S12F: Synthesis of 2-acetyl-3-amino-4-bromo-5-hydroxy-benzofuran (12F)
To a mixture of 12E (6.8 g, 0.021 mol) in MeOH (40 mL) and water (20 mL) was added K2CO3 (4.5 g, 0.032 mol) in batches at room temperature. The reaction mixture was stirred at room temperature overnight, then neutralized with diluted hydrochloric acid to pH=6˜7, extracted with ethyl acetate, dried and concentrated to give 12F (5.6 g, 95.1% yield).
Step S12G: Synthesis of 2-acetyl-3-amino-4-bromo-5-methoxy-benzofuran (12G)
To a mixture of 12F (5.6 g, 0.020 mol) and CsF (9.5 g, 0.0625 mol) in THF (20 mL) was added MeI (2.9 g) dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then added dropwise into water. The solids were precipitated out dissolved in ethyl acetate and purified by column chromatography on silica gel to give 12G (2.4 g, 40.7% yield).
1H-NMR (400 MHz, CDCl3) δ 7.58 (d, J=9.2 Hz, 1H), 7.41 (t, J=9.2 Hz, 1H), 6.41 (s, 2H), 3.89 (s, 3H), 2.38 (s, 3H).
EXAMPLE 13 Intermediate 13 (M13)
Figure US08969373-20150303-C00044
Step S13A: Synthesis of 2-cinnamoyl-3-amino-4-bromo-5-methoxy-benzofuran (13A)
A mixture of 12G (2 g, 0.007 mol), benzaldehyde (1.6 g, 0.015 mol), NaOH (1.2 g) and formaldehyde (20 mL) was heated to 50° C. and reacted overnight, then added into water dropwise. The precipitated solids were collected by filtration to give 13A (2.6 g, 95% yield)
1H-NMR (400 MHz, DMSO-d6) δ 7.81 (m, 2H), 7.37 (d, J=15.6 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.56 (d, J=16.0 Hz, 1H), 7.44-7.50 (m, 4H), 6.82 (s, 2H), 3.91 (s,3H).
Step S13B: Synthesis of 9-bromo-8-methoxy-2-phenyl-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (13B)
A mixture of 13A (2.6 g, 0.0069 mol) in AcOH (10 mL) and H3PO4 (10 mL) was heated to 90° C. and reacted for 2 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 13B (2 g, 76.9% yield).
1H-NMR (400 MHz, DMSO-d6) δ 7.61 (d, J=9.2 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.43 (d, J=9.2 Hz, 1H), 7.33 (t, J=7.2 Hz, 2H), 6.83 (s, 1H), 4.99 (m, 1H), 3.91 (s, 3H), 2.75-2.87 (m, 2H).
Step S13C: Synthesis of 4-hydroxyl-9-bromo-8-methoxy-2-phenyl-benzofuro[3,2-b]pyridine (13C)
A mixture of 13B (2.0 g, 0.0053 mol), FeCl3.6H2O (6 g) and 1,4-dioxane (20 mL) was heated to 110° C. and reacted overnight. After reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 13C (1.8 g, 90.4% yield).
1H-NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 8.17 (d, J=7.6 Hz, 2H), 7.08 (d, J=9.2 Hz, 1H), 7.51-7.54 (m, 3H), 7.42-7.46 (m, 2H), 3.95 (s, 3H).
Step S13D: Synthesis of 9-bromo-4-chloro-8-methoxy-2-phenyl-benzofuro[3,2-b]pyridine (M13)
A mixture of 13C (1.8 g, 0.0048 mol) and POCl3 (10 mL) was heated to 110° C. and reacted for 30 min. TLC monitored the reaction. After the reaction completed, POCl3 in the mixture was evaporated. The residue was added dropwise into ice-water. The solids were collected by filtration and purified by a short column chromatography to give M13 (1.5 g, 79.3% yield).
1H-NMR (400 MHz, CDCl3) δ 8.23 (dd, J1=8.0 Hz, J2=1.6 Hz, 2H), 7.94 (s, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.55 (dt, J1=7.6 Hz, J2=0.8 Hz, 2H), 7.49 (t, J=7.2 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 4.04 (s, 3H).
EXAMPLE 14 Intermediate 14 (M14)
Figure US08969373-20150303-C00045
Step S14A: Synthesis of (E)-1-(3-amino-4-bromo-5-methoxy-benzofuran-2-yl)-3-(2-isopropyl-thiazol-5-yl)-2-propen-1-one (14A)
A mixture of 12G (1.5 g, 5.2 mmol), 2-isopropyl-thiazole-5-carbaldehyde (1.2 g, 7.7 mmol) in THF (20 mL) was cooled to 0° C. To the mixture was added NaOH (1.5 g), then stirred at room temperature overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 14A (1.4 g, 62.9% yield).
Step S14B: Synthesis of 9-bromo-2-(2-isopropyl-thiazol-5-yl)-8-methoxy-1,2-dihydro-benzofuro[3,2-b]pyridin-4-one (14B)
A mixture of 14A (1.4 g, 3.3 mmol), ZnCl2 (6 g), MeCN (10 mL), AcOH (2 mL) and H3PO4 (2 mL) was heated to 90° C. and reacted overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water, extracted with ethyl acetate and concentrated to give 14B (1.1 g, 78% yield).
Step S14C: Synthesis of 4-hydroxyl-9-bromo-2-(2-isopropyl-thiazol-5-yl)-8-methoxy-dibenzofuran (14C)
A mixture of 14B (1.1 g, 2.6 mmol), MnO2 (6 g) in THF (20 mL) was heated to 110° C. and reacted overnight, then filtered. The filtrate was concentrated to give 14C (0.8 g, 73% yield).
Step S14D: Synthesis of 9-bromo-4-chloro-2-(2-isopropyl-thiazol-5-yl)-8-methoxy-benzofuro[3,2-b]pyridine (M14)
A mixture of 14C (0.8 g, 1.9 mmol) in POCl3 (10 mL) was heated to 110° C. and reacted for 30 min. TLC monitored the reaction. After the reaction completed, POCl3 in reaction mixture was evaporated. The residue was added dropwise into ice-water. The precipitated solids were collected by filtration and purified by short column chromatography to give M14 (0.16 g, 19% yield).
1H-NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.81 (s, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 4.04 (s, 3H), 3.40 (m, 1H), 1.52 (d, J=7.2 Hz, 6H).
EXAMPLE 15 Intermediate 15 (M15)
Figure US08969373-20150303-C00046
Step S15A: Synthesis of 1-(3-amino-4-bromo-5-methoxy-benzofuran-2-yl)-3-(2-isopropyl-thiazol-4-yl)-2-propen-1-one (15A)
A mixture of 12G (2 g, 7 mmol), 2-isopropyl-thiazole-4-carbaldehyde (2.2 g, 14.6 mmol), NaOH (1.5 g) and MeOH (20 mL) was heated to 50° C. and reacted overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 15A (2.8 g, 94.4% yield).
1H-NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.67 (d, J=9.2 Hz, 1H), 7.63 (s, 2H), 7.45 (d, J=9.2 Hz, 1H), 6.81 (s, 2H), 3.90 (s, 3H), 3.38 (m, 1H), 1.38 (d, J=6.4 Hz, 6H).
Step S15B: Synthesis of 9-bromo-2-(2-isopropyl-thiazol-4-yl)-8-methoxy-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (15B)
A mixture of 15A (2.8 g, 6.6 mmol), AcOH (10 mL) and H3PO4 (10 mL) was heated to 90° C. and reacted for 2 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 15B (2 g, 71.4% yield).
Step S15C: Synthesis of 4-hydroxyl-9-bromo-2-(2-isopropyl-thiazol-4-yl)-8-methoxy-benzofuro[3,2-b]pyridine (15C)
A mixture of 15B (2.0 g, 4.7 mmol), FeCl3.6H2O (6 g) in 1,4-dioxane (20 mL) was heated to 110° C. and reacted overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 15C (1.2 g, 60.2% yield).
1H-NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.67 (d, J=9.2 Hz, 1H), 7.63 (s, 2H), 7.45 (d, J=9.2 Hz, 1H), 6.81 (s, 2H), 3.91 (s, 3H), 3.38 (m, 1H), 1.42 (d, J=6.4 Hz, 6H).
Step S15D: Synthesis of 9-bromo-4-chloro-2-(2-isopropyl-thiazol-4-yl)-8-methoxy-benzofuro[3,2-b]pyridine (M15)
A mixture of 15C (1.2 g, 2.8 mmol) in POCl3 (10 mL) was heated to 110° C. and reacted for 30 min. TLC monitored the reaction. After the reaction completed, POCl3 in the reaction mixture was evaporated. The residue was added dropwise into ice-water. The precipitated solids were collected by filtration and purified by short column chromatography to give M15 (0.2 g, 16% yield).
1H-NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.20 (s, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.24 (d, J=9.2 Hz, 1H), 4.04 (s, 3H), 3.40 (m, 1H), 1.50 (d, J=7.2 Hz, 6H).
EXAMPLE 16 Intermediate 16 (M16)
Figure US08969373-20150303-C00047
Step S16A: Synthesis of 1-(3-amino-4-bromo-5-methoxy-benzofuran-2-yl)-3-(2-isobutyrylamino-thiazole-4-yl)-2-propen-1-one (16A)
A mixture of 12G (2 g, 7 mmol), 11D (2.8 g, 14.5 mmol) in THF (20 mL) was cooled to 0° C. To the mixture was added NaOH (2 g). The reaction mixture was reacted at room temperature overnight. TLC monitored the reaction. After reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 16A (2 g, 61% yield).
1H-NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 7.65 (s, 1H), 7.35 (d, J=9.2 Hz, 1H), 7.23 (s, 1H), 7.16 (d, J=9.2 Hz, 1H), 6.52 (s, 2H), 3.96 (s, 3H), 2.73 (m, 1H), 1.38 (d, J=7.2 Hz, 6H).
Step S16B: Synthesis of 9-bromo-2-(2-isobutyrylamino-thiazole-4-yl)-8-methoxy-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (16B)
A mixture of 16A (2 g, 4.3 mmol), ZnCl2 (6 g), MeCN (10 mL), AcOH (2 mL) and H3PO4 (2 mL) was heated to 90° C. and reacted overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water, extracted with ethyl acetate and concentrated to give 16B (1.1 g, 55% yield).
1H-NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 7.43 (d, J=9.2 Hz, 1H), 7.17 (d, J=9.2 Hz, 1H), 6.92 (s, 1H), 5.99 (m, 1H), 5.03 (m, 1H), 3.96 (s, 3H), 2.93-3.09 (m, 2H), 2.69-2.74 (m, 1H), 1.33 (d, J=7.2 Hz, 6H).
Step S16C: Synthesis of 4-hydroxyl-9-bromo-2-(2-isobutyrylamino-thiazole-4-yl)-8-methoxy-benzofuro[3,2-b]pyridine (16C)
A mixture of 16B (1.1 g, 2.3 mmol) and MnO2 (6 g) in THF (20 mL) was heated to 110° C. and reacted overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was filtered and the filtrate was concentrated to give 16C (0.7 g, 63.9% yield).
Step S16D: Synthesis of 9-bromo-4-chloro-2-(2-isobutyrylamino-thiazole-4-yl)-8-methoxy-benzofuro[3,2-b]pyridine (M16)
A mixture of 16C (0.7 g, 1.5 mmol) in POCl3 (10 mL) was heated to 110° C. and reacted for 30 min. TLC monitored the reaction. After the reaction completed, POCl3 in the reaction mixture was evaporated. The residue was added dropwise into ice-water. The precipitated solids were collected by filtration and purified by short column chromatography to give M16 (0.2 g, 27% yield).
1H-NMR (400 MHz, CDCl3) δ 9.37 (s, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.63 (d, J=9.2 Hz, 1H), 7.24 (d, J=9.2 Hz, 1H), 4.04 (s, 3H), 2.72 (m, 1H), 1.50 (d, J=7.2 Hz, 6H).
EXAMPLE 17 Intermediate 17 (M17)
Figure US08969373-20150303-C00048
Step S17A: Synthesis of 2-mercapto-4-fluoro-benzonitrile (17A)
The procedure was similar to step S3A, while the starting material was 2,4-difluoro-benzonitrile in stead of 2-fluoro-benzonitrile.
Step S17B: Synthesis of 1-(3-amino-6-fluoro-benzo[b]thiophen-2-yl)-ethanone (17B)
The procedure was similar to step S3B, while the starting material was 17A in stead of 3A.
Step S17C: Synthesis of (E)-2-cinnamoyl-3-amino-6-fluoro-benzo[b]thiophene (17C)
The procedure was similar to step S3C, while the starting material was 17B in stead of 3B.
Step S17D: Synthesis of 2-phenyl-7-fluoro-2,3-dihydro-benzothieno[3,2-b]pyridin-4(1H)-one (17D)
The procedure was similar to step S3D, while the starting material was 17C in stead of 3C.
Step S17E: Synthesis of 2-phenyl-7-fluoro-4-hydroxyl-benzothieno[3,2-b]pyridine (17E)
The procedure was similar to step S3E, while the starting material was 17D in stead of 3D.
17E: MS (ESI): M++1=296.
Step S17F: Synthesis of 4-chloro-7-fluoro-2-phenyl-benzothieno[3,2-b]pyridine (M17)
The procedure was similar to step S3F, while the starting material was 17E in stead of 3E.
M17: MS (ESI): M++1=314.
EXAMPLE 18 Synthesis of 4-chloro-2-methoxycarbonyl-phenyl acetic acid methyl ester (18E)
Figure US08969373-20150303-C00049
Step S18A: Synthesis of 2-carboxyl-phenyl acetic acid (18A)
K2Cr2O7 (24.4 g, 83 mmol) was dissolved in water (360 mL). To the solution was added conc. H2SO4 (133 g, 1.3 mol) dropwise slowly at 65° C., followed by 1H-indene (6.85 g, 56 mmol) dropwise. The reaction mixture was stirred at this temperture for 2 hours. The color of the solution changed from orange to blue, some solids were precipitated out on the bottle wall. The reaction mixture was cooled to below 0° C., and stirred for 2 hours, then filtered. The cake was washed with 1% aq.H2SO4 and ice-water until the green color disappeared, then dried to give 7.6 g of 2-carboxyl-phenyl acetic acid (18A).
MS (ESI): M++1=181.1.
Step S18B: Synthesis of 2-carboxymethyl-5-nitro-benzoic acid (18B)
2-carboxyl-phenyl acetic acid (3 g, 16.7 mmol) was added in batches to fuming HNO3 (16 mL) under ice-salt bath while keeping the temperature under −3° C. The reaction mixture was reacted at that temperature for 2 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was added into ice (16 g) under stirring. The precipitated white solids were collected by filtration and dried to give 2.1 g of the desired product 2-carboxymethyl-5-nitro-benzoic acid (18B).
1H-NMR (DMSO-d6): δ (ppm): 8.62 (d, J=2.8 Hz, 1H), 8.35-8.37 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 4.11 (s, 2H); MS (ESI): M++1=226.1.
Step S18C: Synthesis of 2-methoxycarbonylmethyl-5-nitro-benzoic acid methyl ester (18C)
2-carboxymethyl-5-nitro-benzoic acid (2 g, 8.8 mmol) was dissolved in MeOH (30 mL). To the solution was added SOCl2 (2.64 g, 22.2 mmol) dropwise slowly at room temperature. The reaction mixture was refluxed for 2 hours. TLC monitored the reaction. After the reaction completed, the solvent in the reaction mixture was evaporated to dryness, which was used for the next step directly.
Step S18D: Synthesis of 2-methoxycarbonylmethyl-5-amino-benzoic acid methyl ester (18D)
2-methoxycarbonylmethyl-5-nitro-benzoic acid methyl ester (2.2 g, 8.8 mmol) was dissolved in MeOH (30 mL), then heated to 50° C. To the solution was added SnCl2 (5.89 g, 31 mmol) in batches. The reaction mixture was stirred at this temperture for 1 day. TLC monitored the reaction. After the reaction completed, the solvent was evaporated. To the residue was added ethyl acetate and base, adjusted pH to 8˜9, then filtered though celite and washed with ethyl acetate. The organic layer of the filtrate was collected and washed with water, dried over anhydrous Na2SO4 and concentrated to give 1.3 g of 5-amino-2-methoxycarbonylmethyl-benzoic acid methyl ester (18D).
1H-NMR (DMSO-d6): δ (ppm): 7.15 (d, J=2.8 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H), 6.72 (dd, J1=8 Hz, J2=2.8 Hz, 1H), 5.30 (s, 1H), 3.75 (s, 2H), 3.73 (s, 3H), 3.56 (s, 3H); MS (ESI): M++1=224.2.
Step S18E: Synthesis of 4-chloro-2-methoxycarbonyl-phenyl acetic acid methyl ester (18E)
5-amino-2-methoxycarbonylmethyl-benzoic acid methyl ester (5 g, 22.4 mmol) was dissolved in hydrochloric acid (50 mL). To the solution was added dropwise aq.NaNO2 (1.7 g, 24.6 mmol) at below 5° C. After addition completed, the color became maroon. Then CuCl (2.4 g, 24.6 mmol) solution was added to the reaction mixture. The reaction mixture was reacted at below 5° C. for 1 hour. The reaction mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous Na2SO4, concentrated and purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to give 2.3 g of 5-chloro-2-methoxycarbonylmethyl-benzoic acid methyl ester (18E).
1H-NMR (DMSO-d6): δ (ppm): 7.88 (d, J=2.8 Hz, 1H), 7.64-7.66 (dd, J1=8 Hz, J2=2 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 4.00 (d, J=4.0 Hz, 2H), 3.80 (s, 3H), 3.60 (s, 3H); MS (ESI): M++1=243.7.
EXAMPLE 19 Intermediate 19 (M19)
Figure US08969373-20150303-C00050
Step S19A: Synthesis of 2-(4-chloro-2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (19A)
18E (16.48 mmol) was dissolved in CCl4 (50 mL), and was added NBS (N-bromosuccinimide, 3.23 g, 18.13 mmol), followed by catalytic amount of BPO (benzoyl peroxide). The reaction mixture was refluxed for about 20 hours under stirring. When no more product was produced any more, the reaction mixture was cooled and filtered. To the filtrate was added NBS (1.6 g, 8.24 mmol) and catalytic amount of BPO. The reaction mixture was refluxed for additional 10 hours. After the reaction completed, the mixture was cooled and filtered. The filtrate was concentrated to give 6.4 g of a crude product (19A), which was used directly for the next step.
Step S19B: Synthesis of 3-chloro-benzofuro[3,2-c]isoquinoline-5-ol (19B)
A mixture of 19A (crude, 20.29 mmol) and 2-hydroxy-benzonitrile (20.29 mmol) in MeCN (100 mL) was stirred at room temperature. To the solution was added triethylamine (TEA, 20.44 g, 202.9 mmol) dropwise. After addition completed, the reaction was refluxed for 24 hours, then cooled. The precipitated solids were collected by filtration, washed with a small amount of MeCN, then washed with water several times until there was no TEA salt, dried to give pure product 19B (3.1 g).
1H-NMR (DMSO-d6): δ (ppm): 12.63 (s, 1H), 8.28 (d, J=2.4 Hz, 1H), 8.04-8.07 (m, 2H), 7.95 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H); MS (ESI): M++1=270.7.
Step S19C: Synthesis of 3,5-dichloro-benzofuro[3,2-c]isoquinoline (M19)
A mixture of 19B (11.8 mmol) in POCl3 (20 mL) was refluxed for 2 hours. After reaction completed, POCl3 was evaporated under reduced pressure. The residue was added into crushed ice and stirred for 10 min. The solids were collected by filtration and dried to give 3.2 g of a crude product, which was dissolved in dichloromethane and purified by flash chromatography (petroleum ether 1:1) and concentrated to give a pure product M19 (3.1 g).
1H-NMR (DMSO-d6): δ (ppm): 8.50 (d, J=8.8 Hz, 1H), 8.44 (s, 1H), 8.20 (d, J=7.6 Hz, 1H), 8.13 (dd, J1=9.2 Hz, J2=2.0 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.69 (t, J=7.4 Hz, 1H), 7.59 (t, J=7.4 Hz, 1H); MS (ESI): M++1=289.1.
EXAMPLE 20 Intermediate 20 (M20)
Figure US08969373-20150303-C00051
Step S20A: Synthesis of 2-(4-bromo-2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (20A)
The procedure was similar to step S19A, while the starting material was 5-bromo-2-methoxycarbonylmethyl-benzoic acid methyl ester (the procedure of this compound was similar to 5-chloro-2-methoxycarbonylmethyl-benzoic acid methyl ester, while the starting material was CuBr in stead of CuCl) in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester.
MS (ESI): M++1=367.
Step S20B: Synthesis of 5-hydroxyl-3-bromo-benzofuro[3,2-c]isoquinoline (20B)
The procedure was similar to step S19B, while the starting material was 20A in stead of 19A.
1H-NMR (DMSO-d6): δ (ppm): 12.63 (s, 1H), 8.41 (d, J=1.6 Hz, 1H), 8.05 (d, J=8.0 Hz, 2H), 7.98 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.50-7.54 (t, J=7.6 Hz, 1H), 7.40-7.44 (t, J=7.6 Hz, 1H); MS (ESI): M++1=315.1.
Step S20C: Synthesis of 3-bromo-5-chloro-benzofuro[3,2-c]isoquinoline (M20)
The procedure was similar to step S19C, while the starting material was 20B in stead of 19B.
1H-NMR (DMSO-d6): δ (ppm): 8.59 (d, J=1.6 Hz, 1H), 8.42 (d, J=8.8 Hz, 1H), 8.19-8.24 (m, 2H), 7.95 (d, J=8.0 Hz, 1H), 7.60 (dt, J=1.2, 7.6 Hz, 1H), 7.59 (t, J=7.6 Hz, 1H); MS (ESI): M++1=333.6.
EXAMPLE 21 Intermediate 21 (M21)
Figure US08969373-20150303-C00052
Step S21A: Synthesis of 2-(2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (21A)
The procedure was similar to step S19A, while the starting material was 2-methoxycarbonylmethyl-benzoic acid methyl ester (commercialized) in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester (18E).
MS (ESI): M++1=288.1.
Step S21B: Synthesis of 5-hydroxyl-8-methoxy-benzofuro[3,2-c]isoquinoline (21B)
The procedure was similar to step S19B, while the starting material 19A and 2-hydroxy-benzonitrile were replaced with 21A and 2-hydroxy-5-methoxy-benzonitrile, respectively.
1H-NMR (DMSO-d6): δ (ppm): 12.32 (s, 1H), 8.34 (d, J=8.0 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.88 (t, J=8.4 Hz, 1H), 7.67 (d, J=9.2 Hz, 1H), 7.59-7.62 (m, 2H), 7.09 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 3.83 (s, 3H); MS (ESI): M++1=266.3.
Step S21C: Synthesis of 8-methoxy-5-chloro-benzofuro[3,2-c]isoquinoline (M21)
The procedure was similar to step S19C, while the starting material was 21B in stead of 19B.
1H-NMR (DMSO-d6): δ (ppm): 8.50 (t, J=9.0 Hz, 2H), 8.12 (t, J=8.0 Hz, 1H), 7.96 (t, J=8.0 Hz, 1H), 7.86 (d, J=9.2 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.25 (dd, J1=9.2 Hz, J2=2.8 Hz, 1H), 3.93 (s, 3H); MS (ESI): M++1=284.7.
EXAMPLE 22 Intermediate 22 (M22)
Figure US08969373-20150303-C00053
Step S22A: Synthesis of 2-(2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (22A)
The procedure was similar to step S19A, while the starting material was 2-methoxycarbonylmethyl-benzoic acid methyl ester (commercialized) in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester (18E).
Step S22B: Synthesis of 5-hydroxyl-benzofuro[3,2-c]isoquinoline 1 (22B)
The procedure was similar to step S19B, while the starting material was 22A in stead of 19A.
Step S22C: Synthesis of 5-chloro-benzofuro[3,2-c]isoquinoline (M22)
The procedure was similar to step S19C, while the starting material was 22B in stead of 19B.
1H-NMR (DMSO-d6): δ (ppm): 8.48 (d, J=6.4 Hz, 2H), 8.20 (d, J=7.2 Hz, 1H), 8.12 (t, J=7.6 Hz, 1H), 7.90-7.95 (m, 2H), 7.68 (t, J=7.8 Hz, 1H), 7.58 (t, J=7.2 Hz, 1H), MS (ESI): M++1=254.7.
EXAMPLE 23 Intermediate 23 (M23)
Figure US08969373-20150303-C00054
Step S23A: Synthesis of 2-(2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (23A)
The procedure was similar to step S19A, while the starting material was 2-methoxycarbonylmethyl-benzoic acid methyl ester (commercialized) in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester (18E).
Step S23B: Synthesis of 5-hydroxyl-benzothieno[3,2-c]isoquinoline (23B)
The procedure was similar to step S19B, while the starting material was 23A in stead of 19A, and used 2-mercapto-benzonitrile in stead of 2-hydroxy-benzonitrile.
Step S23C: Synthesis of 5-chloro-benzothieno[3,2-c]isoquinoline (M23)
The procedure was similar to step S19C, while the starting material was 23B in stead of 19B.
1H-NMR (DMSO-d6): δ (ppm): 8.51 (d, J=8.4 Hz, 1H), 8.41 (m, 1H), 8.31 (dd, J1=7.2 Hz, J2=0.8 Hz, 1H), 8.24 (m, 1H), 8.09 (t, J=8.0 Hz, 1H), 7.96 (t, J=8.0 Hz, 1H), 7.65-7.68 (m, 2H); MS (ESI): M++1=270.7.
EXAMPLE 24 Intermediate 24 (M24)
Figure US08969373-20150303-C00055
Step S24A: Synthesis of 2-(2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (24A)
The procedure was similar to step S19A, while the starting material was 2-methoxycarbonylmethyl-benzoic acid methyl ester in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester (18E).
Step S24B: Synthesis of 5-hydroxyl-8-chloro-benzofuro[3,2-c]isoquinoline (24B)
The procedure was similar to step S19B, while the starting material was 24A in stead of 19A, and used 5-chloro-2-hydroxy-benzonitrile in stead of 2-hydroxy-benzonitrile.
Step S24C: Synthesis of 5,8-dichloro-benzofuro[3,2-c]isoquinoline (M24)
The procedure was similar to step S19C, while the starting material was 24B in stead of 19B.
1H-NMR (DMSO-d6): δ (ppm): 8.51 (t, J=17.2 Hz, 2H), 8.23 (d, J=2.0 Hz, 1H), 8.15 (t, J=16.0 Hz, 1H), 7.96-7.99 (m, 2H), 7.70 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H); MS (ESI): M++1=289.1.
EXAMPLE 25 Intermediate 25 (M25)
Figure US08969373-20150303-C00056
Step S25A: Synthesis of 2-(4-methoxyl-2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (25A)
The procedure was similar to step S19A, while the starting material was 5-methoxyl-2-methoxycarbonylmethyl-benzoic acid methyl ester (commercialized) in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester (18E).
MS (ESI): M++1=318.1.
Step S25B: Synthesis of 5-hydroxyl-3-methoxy-benzofuro[3,2-c]isoquinoline (25B)
The procedure was similar to step S19B, while the starting material was 25A in stead of 19A.
MS (ESI): M++1=266.3.
Step S25C: Synthesis of 3-methoxy-5-chloro-benzofuro[3,2-c]isoquinoline (M25)
The procedure was similar to step S19C, while the starting material was 25B in stead of 19B.
1H-NMR (CDCl3): δ (ppm): 8.336 (d, J=8.8 Hz, 1H), 8.242 (d, J=7.6 Hz, 1H), 7.746 (d, J=2.4 Hz, 1H), 7.711 (d, J=7.6 Hz, 1H), 7.53-7.58 (m, 2H), 7.48 (t, J=7.2 Hz, 1H), 4.06 (s, 3H); MS (ESI): M++1=284.7.
EXAMPLE 26 Intermediate 26 (M26)
Figure US08969373-20150303-C00057
Step S26A: Synthesis of 2-(4-chloro-2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (26A)
The procedure was similar to step 19A.
Step S26B: Synthesis of 5-hydroxyl-3-chloro-8-methoxy-benzofuro[3,2-c]isoquinoline (26B)
The procedure was similar to step S19B, while the starting material was 2-hydroxy-5-methoxy-benzonitrile in stead of 2-hydroxy-benzonitrile.
1H-NMR (DMSO-d6): δ (ppm): 12.49 (s,1H), 8.25 (d, J=2.0 Hz, 1H), 8.027 (d, J=8.8 Hz, 1H), 7.918 (dd, J1=8.8 Hz, J2=2 Hz, 1H), 7.669 (d, J=9.2 Hz, 1H), 7.587 (d, J=2.8 Hz, 1H), 7.097 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H), 3.840 (s, 3H); MS (ESI): M++1=300.7.
Step S26C: Synthesis of 3,5-dichloro-8-methoxy-benzofuro[3,2-c]isoquinoline (M26)
The procedure was similar to step S19C, while the starting material was 26B in stead of 19B.
1H-NMR (CDCl3): δ (ppm): 8.502 (d, J=1.6 Hz, 1H), 8.360 (d, J=8.8 Hz, 1H), 8.871 (dd, J1=8.8 Hz, J2=1.6 Hz, 1H), 7.706 (s, J=2.4 Hz, 1H), 7.623 (d, J=9.2 Hz, 1H), 7.182 (dd, J1=9.2 Hz, J2=2.8 Hz, 1H), 3.964 (s, 3H); MS (ESI): M++1=319.2.
EXAMPLE 27 Intermediate 27 (M27)
Figure US08969373-20150303-C00058
Step S27A: Synthesis of 2-(4-chloro-2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (27A)
The procedure was similar to step 19A.
Step S27B: Synthesis of 3,8-dichloro-5-hydroxyl-benzofuro[3,2-c]isoquinoline 1 (27B)
The procedure was similar to step S19B, while the starting material was 5-chloro-2-hydroxy-benzonitrile in stead of 2-hydroxy-benzonitrile.
1H-NMR (DMSO-d6): δ (ppm): 12.539 (s, 1H), 8.246 (d, J=2.0 Hz, 1H), 8.039 (s, 1H), 8.028 (d, J=8.8 Hz, 1H), 7.926 (dd, J1=8.4 Hz, J2=2 Hz, 1H), 7.796 (d, J=8.8 Hz, 1H), 7.520 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H); MS (ESI): M++1=305.1.
Step S27C: Synthesis of 3,5,8-trichloro-benzofuro[3,2-c]isoquinoline (M27)
The procedure was similar to step S19C, while the starting material was 27B in stead of 19B.
1H-NMR (CDCl3): δ (ppm): 8.510 (d, J=2.0 Hz, 1H), 8.356 (d, J=8.8 Hz, 1H), 8.220 (d, J=1.6 Hz, 1H), 7.890 (dd, J1=8.8 Hz, J2=1.6 Hz, 1H), 7.655 (d, J=8.8 Hz, 1H), 7.540 (dd, J1=8.4 Hz, J2=2 Hz, 1H); MS (ESI): M++1=323.6.
EXAMPLE 28 Intermediate 28 (M28)
Figure US08969373-20150303-C00059
Step S28A: Synthesis of 2-(4-methoxyl-2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (28A)
The procedure was similar to step S19A, while the starting material was 5-methoxy-2-methoxycarbonylmethyl-benzoic acid methyl ester (commercialized) in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester (18E).
MS (ESI): M++1=318.1.
Step S28B: Synthesis of 5-hydroxyl-3-methoxy-8-chloro-benzofuro[3,2-c]isoquinoline (28B)
The procedure was similar to step S19B, while the starting material was 28A in stead of 19A, and used 5-chloro-2-hydroxy-benzonitrile in stead of 2-hydroxy-benzonitrile.
Step S28C: Synthesis of 3-methoxy-5,8-dichloro-benzofuro[3,2-c]isoquinoline (M28)
The procedure was similar to step S19C, while the starting material was 28B in stead of 19B.
1H-NMR (CDCl3): δ (ppm): 8.325 (d, J=8.8 Hz, 1H), 8.204 (d, J=2.0 Hz, 1H), 7.761 (d, J=2.4 Hz, 1H), 7.634 (d, J=8.8 Hz, 1H), 7.591 (dd, J1=8.8 Hz, J2=2 Hz, 1H), 7.495 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 4.070 (s, 3H); MS (ESI): M++1=319.1.
EXAMPLE 29 Intermediate 29 (M29)
Figure US08969373-20150303-C00060
Step S29A: Synthesis of 2-(2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (29A)
The procedure was similar to step S19A, while the starting material was 2-methoxycarbonylmethyl-benzoic acid methyl ester in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester (18E).
Step S29B: Synthesis of 5-hydroxyl-9-fluoro-benzothieno[3,2-c]isoquinoline (29B)
The procedure was similar to step S19B, while the starting material was 29A in stead of 19A, and used 4-fluoro-2-mercapto-benzonitrile in stead of 2-hydroxy-benzonitrile.
Step S29C: Synthesis of 5-chloro-9-fluoro-benzothieno[3,2-c]isoquinoline (M29)
The procedure was similar to step S19C, while the starting material was 29B in stead of 19B.
1H-NMR (CDCl3): δ (ppm): 8.47 (d, J=8.4 Hz, 1H), 8.37 (m, 1H), 8.27 (d, J=8.0 Hz, 1H), 8.171 (d, J=8.4 Hz, 1H), 8.05 (dd, J1=8.0 Hz, J2=7.2 Hz, 1H), 7.49 (dd, J1=8.4 Hz, J2=8.0 Hz, 1H); MS(ESI): M++1=288.
EXAMPLE 30˜70 Synthesis of Compound Ik (k=1, 2, 3 . . . 13, 15 . . . 41, 42) Synthetic Method A
A mixture of intermediate Mi (I=1, 2, 3, . . . 11, 13, . . . 17, 19, . . . or 29) (0.1 mmol), starting material A-j (j=I, II, . . . or VI) (0.1 mmol) and t-BuOK (potassium tert-butoxide, 5 mmol) was cooled to 0° C. To the mixture was added DMSO (dimethyl sulfoxide, 5 mL), then warmed to room temperature within 20 min. TLC monitored the reaction. After the reaction completed, the reaction mixture was poured into ice-water, extracted with ethyl acetate (50 mL×3), dried over anhydrous Na2SO4, filtered, concentrated to dryness under reduced pressure and purified by preparative-TLC (silica gel, CH2Cl2: MeOH=100:5) to give desired product Ik.
Synthetic Method B
A mixture of starting material A-j (j=I, II, . . . or VI) (1 mmol) and t-BuOK (5 mmol) was dissolved in THF (tetrahydrofuran) and DMSO (2 ml+2 mL) and cooled to 0° C. To the solution was added a solution of intermediate Mi (I=1, 2, 3, . . . 11, 13, . . . 17, 19, . . . or 29) (1 mmol) in THF/DMSO (2 ml, 1/1) dropwise within 5 min at 0° C. The reaction mixture was stirred at room temperature overnight, then poured into water, extracted with ethyl acetate, dried over anhydrous MgSO4 and purified by preparative-HPLC.
wherein, A-j (j=I, II, . . . or VI) (The references of preparation: 1) PCT Int. Appl., 2009140500, 19 Nov. 2009; 2) PCT Int. Appl., 2008008776, 17 Jan. 2008) was listed as follows:
Figure US08969373-20150303-C00061
Figure US08969373-20150303-C00062
TABLE 1
Synthetic
Example Ik A-j Mi method Compoud Structure M+ + 1
30  1 A-II M2  A
Figure US08969373-20150303-C00063
 		850.3
31  2 A-I M21 A
Figure US08969373-20150303-C00064
 		816
32  3 A-II M4  A
Figure US08969373-20150303-C00065
 		830
33  4 A-II M5  A
Figure US08969373-20150303-C00066
 		834
34  5 A-I M24 A
Figure US08969373-20150303-C00067
 		820.2
35  6 A-I M22 A
Figure US08969373-20150303-C00068
 		786.3
36  7 A-II M17 A
Figure US08969373-20150303-C00069
 		834.2
37  8 A-II M6  A
Figure US08969373-20150303-C00070
 		878.2
38  9 A-II M3  A
Figure US08969373-20150303-C00071
 		816.3
39 10 A-I M28 A
Figure US08969373-20150303-C00072
 		820.2
40 11 A-II M24 A
Figure US08969373-20150303-C00073
 		808.2
41 12 A-II M28 A
Figure US08969373-20150303-C00074
 		808.2
42 13 A-III M24 A
Figure US08969373-20150303-C00075
 		807.2
43 15 A-II M21 A
Figure US08969373-20150303-C00076
 		804.3
44 16 A-I M20 B
Figure US08969373-20150303-C00077
 		865.1
45 17 A-I M19 B
Figure US08969373-20150303-C00078
 		820.3
46 18 A-I M25 B
Figure US08969373-20150303-C00079
 		816.3
47 19 A-I M26 B
Figure US08969373-20150303-C00080
 		850.2
48 20 A-IV M19 B
Figure US08969373-20150303-C00081
 		820.2
49 21 A-IV M4  A
Figure US08969373-20150303-C00082
 		842.3
50 22 A-IV M8  A
Figure US08969373-20150303-C00083
 		876.3
51 23 A-II M8  A
Figure US08969373-20150303-C00084
 		864.3
52 24 A-II M10 B
Figure US08969373-20150303-C00085
 		913.3
53 25 A-II M10 A
Figure US08969373-20150303-C00086
 		929.2
54 26 A-II M15 A
Figure US08969373-20150303-C00087
 		973.2
55 27 A-II M13 A
Figure US08969373-20150303-C00088
 		908.2
56 28 A-IV M13 A
Figure US08969373-20150303-C00089
 		920.2
57 29 A-II M19 B
Figure US08969373-20150303-C00090
 		808.2
58 30 A-II M20 B
Figure US08969373-20150303-C00091
 		852.2
59 31 A-II M25 B
Figure US08969373-20150303-C00092
 		804.3
60 32 A-II M26 B
Figure US08969373-20150303-C00093
 		838.2
61 33 A-II M27 B
Figure US08969373-20150303-C00094
 		842.2
62 34 A-II M11 A
Figure US08969373-20150303-C00095
 		956.3
63 35 A-II M16 A
Figure US08969373-20150303-C00096
 		1000.2
64 36 A-V M1  A
Figure US08969373-20150303-C00097
 		822.3
65 37 A-VI M1  A
Figure US08969373-20150303-C00098
 		810.3
66 38 A-II M1  A
Figure US08969373-20150303-C00099
 		800.3
67 39 A-II M9  A
Figure US08969373-20150303-C00100
 		929.2
68 40 A-II M14 A
Figure US08969373-20150303-C00101
 		973.2
69 41 A-II M23 A
Figure US08969373-20150303-C00102
 		780.2
70 42 A-II M28 B
Figure US08969373-20150303-C00103
 		838.2
Compound 2 tert-butyl(2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(8-methoxybenzofuro[3,2-c]isoquinolin-5-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl carbamate
1H-NMR (CDCl3): δ (ppm): 10.29 (s, 1H), 8.33 (d, J=8.2 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.78 (t, J=7.6 Hz, 1H), 7.49-7.55 (m, 3H), 7.08 (d, J=9.0 Hz, 1H), 6.96 (s, 1H), 6.11 (s, 1H), 5.70 (dd, J=8.8, 8.0 Hz, 1H), 5.20 (m, 1H), 4.98 (t, J=9.6 Hz, 1H), 4.67-4.72 (m, 2H), 4.33 (m, 1H), 4.12 (d, J=9.3 Hz, 1H), 3.99 (s, 3H), 2.80-2.92 (m, 2H), 2.73-2.78 (m, 1H), 2.49-2.59 (brs, 1H), 2.28 (q, J=8.8 Hz, 1H), 1.70-1.95 (m,3H), 1.55-1.65 (m, 1H), 1.40-1.52 (m, 7H), 1.28 (s, 10H), 1.08-1.15 (m, 2H), 0.91 (m, 1H); MS (ESI): M++1=816.
Compound 3 tert-butyl(S)-1-((2S,4R)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-(8-methoxy-2-phenylbenzofuro [3,2-b]pyridin-4-yloxy)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl carbamate
1H-NMR (CDCl3): δ (ppm): 9.27 (s, 1H), 8.02 (d, J=6.8 Hz, 2H), 7.82 (d, J=2.5 Hz, 1H), 7.69 (s, 1H), 7.61-7.65 (m, 4H), 7.33 (d, J=9.2 Hz, 1H), 5.84 (brs, 1H), 5.71 (dd, J=18.3, 9.6 Hz, 1H), 5.30 (d, J=18.3 Hz, 1H), 5.13 (d, J=9.6 Hz, 1H), 4.56-4.62 (m, 2H), 3.95-4.18 (m, 2H), 3.94 (s, 3H), 2.91-2.97 (m, 1H), 2.71 (dd, J=6.7, 14.1 Hz, 1H), 2.57 (ddd, J=14.1, 10.8, 4.1 Hz, 1H), 2.23 (dd, J=8.1, 17.5 Hz, 1H), 1.89 (dd, J=5.5, 17.8 Hz, 1H), 1.45 (dd, J=5.3, 9.2 Hz, 1H), 1.21-1.27 (m, 2H), 1.10 (s, 11H), 1.02 (s, 9H); MS (ESI): M++1=830.
Compound 4 tert-butyl(S)-1-((2S,4R)-4-(8-chloro-2-phenylbenzofuro[3,2-b]pyridin-4-yloxy)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl carbamate
1H-NMR (CDCl3): δ (ppm): 9.27 (s, 1H), 8.30 (s, 1H), 8.04 (d, J=8.4 Hz, 2H), 7.61-7.70 (m, 3H), 7.51-7.58 (m, 3H), 5.71-5.80 (m, 2H), 5.30 (d, J=16.7 Hz, 1H), 5.13 (d, J=10.4 Hz, 1H), 4.52-4.62 (m, 2H), 3.20 (s, 1H), 4.13 (d, J=10.0 Hz, 1H), 2.91-2.97 (m, 1H), 2.67 (dd, J=6.8, 13.9 Hz, 1H), 2.57 (ddd, J=14.1, 10.8, 4.1, 1H), 2.23 (dd, J=8.1, 17.5 Hz, 1H), 1.88 (dd, J=5.5, 17.8 Hz, 1H), 1.45 (dd, J=5.3, 9.2 Hz, 1H), 1.21-1.27 (m, 2H), 1.12 (s, 11H), 1.02 (s,9H); MS (ESI): M++1=834.
EXAMPLE 71 Compound 14 Synthesis of (2S,4R)-1-((S)-2-tert-butyl-4-oxo-4-(piperidin-1-yl)butanoyl)-4-(8-chlorobenzofuro[3,2-c]isoquinolin-5-yloxy)-N-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropyl)pyrrolidine-2-carboxamide
Figure US08969373-20150303-C00104
A mixture of compound 13 (40.4 mg, 0.05 mmol) and LiOH (5 eq) was dissolved in THF/MeOH/H2O (3 mL/3 mL/3 mL) and stirred at room temperature for 3 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was acidified with 1N hydrochloric acid to pH˜7, then extracted with ethyl acetate, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. The residue was dissolved in dimethylfomamide, then piperidine (0.1 mmol),
o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.065 mmol) and N,N-diisopropyl ethylamine (0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight, then poured into water, extracted with ethyl acetate (50 mL×3), dried over MgSO4 and purified by flash chromatography to give desired product 14.
1H-NMR (CDCl3): δ (ppm): 10.21 (s, 1H), 8.50 (d, J=8.4 Hz, 1H), 8.24 (d, J=8.0 Hz, 1H), 8.01 (brs, 1H), 7.82 (t, J=8.0 Hz, 1H), 7.54-7.60 (m, 2H), 7.43 (dt, J=8.8, 1.2 Hz, 1H), 7.14 (brs, 1H), 6.06 (brs, 1H), 5.75-5.83 (m, 1H), 5.25 (m, d, J=17.2 Hz, 1H), 5.13 (d, J=10.0 Hz, 1H), 4.63 (d, J=11.6 Hz, 1H), 4.51 (t, J=8.0 Hz, 1H), 4.14 (dd, J=8.8, 2.0 Hz, 1H), 3.63 (s, 2H), 3.05-3.20 (m, 2H), 2.86-3.00 (m, 2H), 2.68-2.73 (m, 1H), 2.57-2.63 (m, 1H), 2.35 (d, J=14.4 Hz, 1H), 2.06-2.13 (m, 1H), 1.99 (t, J=8.0 Hz, 1H), 1.43-1.60 (m, 5H), 1.28-1.42 (m, 4H), 0.9-1.10 (m, 11H); MS (ESI): M++1=818.3.
EFFECT EXAMPLE 1 In Vitro Inhibitory Activity of Compounds in HCV Replication in HCV Infected Human Hepatocellular Carcinoma Cells (Huh7.5.1)
The preparation of Huh7.5.1cells: Huh 7.5.1 cells were seeded at a 96-well plate with 37 and 5% CO2 for 24 hours incubation.
Virus infection: Using the J399EM virus supernatants (moi≈0.1) to infect Huh7.5.1cells. At the same time, the no virus infected cell will be set up as the control. After 8 hours virus infection, the virus will be washed out with PBS.
Drug treatment: The different doses of samples (i.e. the compound Ik, wherein k=1, 2, 3, . . . 42) were added in J399EM infected Huh7.5.1 cells, the each dose for duplicate. At the same time the no sample added in wells will be set up as the control. The test dose of sample is starting from 25 nM or 400 nM, with quarter dilution, 5 doses of sample will be added in the test wells, respectively, then continued for 72 hours incubation.
HCV-EGFP fluorescence detection: After samples treatment for 72 hours, the autofluorescence of HCV-EGFP were measured by the luminometer with excitation of 488 nm, and emission of 516 nm. The related fluorescence unit (RFU) of samples will be read out and used for calculating the inhibitory rates of compounds in HCV replication.
EFFECT EXAMPLE 2 The Inhibitory Activity of Compounds in the HCV Replicon System
HCV replicon cell-line: The Huh7 cells were transfected with pSGR-399LM replicon DNA and cultured in the DMEM containing 10% FBS and 0.5 mg/mL G418. The cells were split at 1:3 to 1:5 every 3-4 days. The transfected cells were seeded in 96-well plates and cultured at 37° C., 5% CO2 for 24 hr.
Treatment with samples: To the HCV replicon Huh7 cells-line were added different concentration of the samples (i.e. compound Ik, wherein k=1, 2, 3 . . . 42), the each concentration for duplicate, and set no sample control wells. The concentration started at 400 nM, with quarter dilution to form five different concentrations of samples, that is 400 nM, 100 nM, 25 nM, 6.25 nM and 1.56 nM. The samples were added separately, and continued to incubated for 72 hr.
Fluorescence detection: After 72 hr treatment with sample, the cells were lysed and added with Renilla luciferase substrate to detect luminescent signal. The relative luminescent unit (RLU) in the luminometer was read out and used to calculate the inhibition rate of HCV.
TABLE 2
HCV infected
human
HCV hepatocellular
MS(ESI): replicon system carcinoma cells in
compound M+ + 1 EC50(nM) vitro EC50(nM)
1 850 B B
2 816 A A
3 830 A B
4 834 A B
5 820 A A
6 786 A A
7 834 A A
8 878 A B
9 816 A B
10 820 A A
11 808 A B
12 808 A B
13 807 B B
14 818 A B
15 804 B B
16 865 A A
17 820 A A
18 816 A A
19 850 A A
20 820 A A
21 842 A B
22 876 A A
23 864 A A
24 913 A A
25 929 A A
26 973 A A
27 908 A A
28 920 A A
29 808 A A
30 852 B B
31 804 B B
32 838 A B
33 842 B B
34 956 A A
35 1000 A A
36 822 A B
37 810 B B
38 800 A A
39 929 A A
40 973 A A
41 780 — —
42 838 — —
A: EC50 ≦ 100 nM,
B: 100 nM < EC50 < 1000 nM
EFFECT EXAMPLE 3 Pharmacokinetic Evaluation of the Compounds of this Invention Experimental
Twenty healthy male Sprague-Dawley (SD) rats with body weight of 200-220 g were divided into 5 groups randomly and each group contains 4 rats. Before the experiment, rats were fasted for 12 h with free access to water. The compound Ik (wherein k=2, 5, 18, 34 or 38) of this invention was administered by oral gavage at a dose level of 10 mg/kg. The compounds were prepared with 0.5% CMC-Na containing 1% Tween 80. The dose volume was 10 mL/kg. The rats were afforded unlimited access to food after 2 h of dosing 0.3 mL of blood samples were collected at 0.25 h, 0.5 h, 1.0 h, 2.0 h, 3.0 h, 5.0 h, 7.0 h, 9.0 h, and 24.0 h, respectively, from postocular venous plexes of the rat. The blood samples were placed in heparin-containing tubes and immediately centrifuged at 11000 rpm for 5 min. Plasma was separated and refrigerated at −20° C. until analysis. LC-MS/MS methods were used to quantify plasma concentrations of the compound Ik. The pharmacokinetic parameters obtained are shown in Table 3.
TABLE 3
Pharmacokinetic parameters of SD rats after oral administration
Tmax Cmax AUC0−t AUC0−∞ t1/2 F
Compound (h) (ng/mL) (ng · h/mL) (ng · h/mL) (h) (%)
I38 0.63 ± 0.25 150 ± 42 239 ± 81  243 ± 81 0.72 ± 0.30 8.7
I5 1.25 ± 0.50  560 ± 139  2882 ± 1720   3028 ± 1705 3.48 ± 1.09 17.1
I18 1.7 ± 0.6 623.3 ± 60.7 3218.5 ± 336.4  3266.8 ± 303.2 3.8 ± 1.0 36.1
I34 0.4 ± 0.2  11.4 ± 4.3   9.6 ± 0.9  11.0 ± 1.1 0.5 ± 0.3 1.6
I2 0.4 ± 0.1  49.7 ± 11.0 157.9 ± 49.8 1777.6 ± 53.7 3.1 ± 1.3 1.8
Experimental Conclusions
The compounds of this invention showed satisfied pharmacokinetic behaviour. For instance, Compound I18 was orally administered to SD rats at 10 mg/kg. The peak plasma concentration was at 1.7±0.6 h, with Cmax of 623±60.7 ng/mL, and the area under plasma concentration-time curves AUC0-t was 3218.5±336.4 ng·h/mL, AUC0-∞ was 3266.8±303.2 ng·h/mL. The elimination half-life t1/2 was 3.8±1.0 h. The absolute bioavailability F approached to 36.1%.
INDUSTRIAL APPLICABILITY OF THE INVENTION
The compounds of the present invention have the excellent activity of anti-hepatitis C virus. The value EC50 of the desired compounds for HCV replicon system (pSGR-399LM+Huh7.5) all are lesser than 1000 nM. A majority of compounds are lesser than 100 nM. The value EC50 of the compounds for HCV infected human hepatocellular carcinoma cells (Huh7.5.1) in vitro all are lesser than 1000 nM also. And the compounds of this invention showed satisfied pharmacokinetic behaviour also.

Claims (19)

What is claimed is:
1. A compound having the formula (I):
Figure US08969373-20150303-C00105
or a pharmaceutically acceptable salt thereof, wherein,
A is O, S, CH, NH or NR′, wherein, R′ is C1-C6 alkyl which can be substituted by halogen;
Z1 is N or CRZ1, Z2 is CRZ2, wherein, RZ1 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, NH2, (C1-C6 alkyl)NH or (C1-C6 alkyl)2N, RZ2 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, 6-10 membered aryl or 5-10 membered heteroaryl having 1-4 heteroatoms selected from O, N and S; or RZ1, RZ2 with carbon atoms linking with them together form a 5-8 membered simple carbon ring or double carbon ring which can be inserted by 1-3 heteroatoms selected from N, O and S, and which can be substituted by Re, Rf, Rg, or Rh, wherein the definition of Re, Rf, Rg, and Rh is the same as that of Ra, Rb, Rc and Rd;
Ra, Rb, Rc and Rd independently is H, OH, halogen or —Y1—Rm, Y1 is linking bond, O, S, SO, SO2 or NRn; Rm is hydrogen, or a substituent which can be substituted by 1-5 Rm′ selected from the following group: (C1-C8) alkyl, N≡C—(C1-C6) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) cycloalkyl, (C3-C7 cycloalkyl) (C1-C6) alkyl, and 5˜6 membered aryl or heteroaryl having 1-2 heteroatom(s) independently selected from N, O, S; Rn is H, (C1-C6) alkyl or (C3-C6) cycloalkyl; Rm′ is a substituent selected from the following group: halogen, (C1-C6) alkyl substituted optionally by (C1-C6)alkyl-O— or (C3-C6) cycloalkyl-O—, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, (C1-C6) alkyl-O—, —NH2, (C1-C4 alkyl)NH_ and (C1-C4 alkyl)2N—;
A1 is NH or CH2;
A2 is N, O or linking bond;
R1′ is a substituent which can be substituted by 1 or more R1″ selected from the following group: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, (6-10 membered aryl) C1-C2 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl) C1-C2 alkyl, C3-C7 cycloalkenyl, (C3-C7 cycloalkenyl) C1-C2 alkyl, 4-7 membered heterocycl having 1-4 heteroatoms selected from O, S and N, (4-7 membered heterocycl having 1-4 heteroatoms selected from O, S, and N) C1-C2 alkyl, C5-C10 heteroaryl and (C5-C10 heteroaryl) C1-C2 alkyl; R1″ is a substituent selected from the following group: halogen, OH, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, —NH2, (C1-C6 alkyl)—NH—and —N(C1-C6 alkyl)2;
R1 is hydrogen; or; R1 linking covalently with R3 together forms a C5-C9 saturated or unsaturated hydrocarbon chain which can be inserted by 0˜2 heteroatom(s) independently selected from N, S and O, or which can be substituted by none or more halogen, O, S or —NRpRq, wherein, Rp and Rq independently is hydrogen or C1-C6 alkyl;
R3 is C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 4-7 membered heterocycl having 1-4 heteroatoms selected from O, S, and N, (C3-C7 cycloalkyl) C1-C4 alkyl, (C3-C7 cycloalkenyl) C1-C4 alkyl, (4-7 membered heterocycl having 1-4 heteroatoms selected from O, S and N) C1-C4 alkyl, C2-C6 alkylacyl, (C1-C4 alkyl)1-2 (C3-C7) cycloalkyl or (C1-C6 alkyl)1-2 amino; and
R4 is C1-C10 alkoxycarbonyl, (C1-C10 alkyl)NHCO, (C1-C10 alkyl)2NCO, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms selected from O, N and S or formyl substituted by 3˜7 membered cycloalkyl, 4-7 membered heterocycl having 1-4 heteroatoms selected from O, S, and N or cycloalkoxy, which can be substituted by 1 or more R4′; R4′ is a substituent selected from the following group: halogen, OH, ON CN, C1-C6 alkyl, C2-C6 alkynyl, C1-C6 alkoxyl, —NH2, (C1-C6 alkyl)—NH— and —N(C1-C6 alkyl)2, (C1-C6 alkyl)—SO2—.
2. The compound as claimed in claim 1, characterized in that when Z3 links with O, RZ1, RZ2 with carbon atoms linking with them together form a 6 membered aromatic ring substituted by Re, Rf, Rg and Rh, therefore, the structure of the compound having the general formula (I) is shown in formula (Ia),
Figure US08969373-20150303-C00106
wherein, the definition of Re, Rf, Rg and Rh is the same as that of Ra, Rb, Rc and Rd.
3. The compound as claimed in claim 1, characterized in that when Z1 links with O, the structure of the compound having the general formula (I) is shown in formula (Ib1),
Figure US08969373-20150303-C00107
wherein, R3 is C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, heterocycloalkyl, (C3-C7 cycloalkyl) C1-C4 alkyl, (C3-C7 cycloalkenyl) C1-C4 alkyl, (heterocycloalkyl) C1-C4 alkyl, C2-C6 alkylacyl, (C1-C4 alkyl)1-2(C3-C7) cycloalkyl or (C1-C6 alkyl)1-2 amino.
4. The compound as claimed in claim 1, characterized in that when Z1 links with O, the structure of the compound having the general formula (I) is shown in formula (Ib2),
Figure US08969373-20150303-C00108
wherein, R1 linking covalently with R3 together forms a C5-C9 saturated or unsaturated hydrocarbon chain which can be inserted by 0˜2 heteroatom(s) independently selected from N, S and O, or which can be substituted by none or more halogen, O, S or —NRpRq, wherein, Rp and Rq independently is hydrogen or C1-C6 alkyl.
5. The compound as claimed in claim 3, characterized in that Ar is a 6 membered aryl or a 5˜6 membered heteroaryl which is substituted optionally by 1 or more RAr; wherein, RAr is selected from the following substituent group: halogen, amino, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 hydroxyalkyl and (C1-C6) alkylamido.
6. The compound as claimed in claim 2, characterized in that Rm is a substituent which can be substituted by 1˜3 Rm′ selected from the following group: C1-C8 alkyl, N≡C—(C1-C6) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) cycloalkyl, (C3-C7 cycloalkyl) (C1-C6) alkyl, and 5˜6 membered aryl or heteroaryl having 1-2 heteroatom(s) independently selected from N, O, S; Rm′ is a substituent selected from the following group: halogen, (C1-C6) alkyl substituted optionally by (C1-C6)alkyl—O— or (C3-C6)cycloalkyl—O—, (C1-C6) haloalkyl, (C3-C7)cycloalkyl, (C1-C6)alkyl—O—, —NH2, (C1-C4 alkyl)NH— and (C1-C4 alkyl)2N—.
7. The compound as claimed in claim 2, characterized in that R1′ is a substituent which can be substituted by 1 or more R1″ selected from the following group: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-8 membered aryl, (6-8 membered aryl) C1-C2 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl) C1-C2 alkyl, C3-C7 cycloalkenyl, (C3-C7 cycloalkenyl) C1-C2 alkyl, 4-6 membered heterocycl having 1-3 heteroatoms selected from O,S, and N, (4-6 membered heterocycle having 1-3 heteroatoms selected from O, S and N) C1-C2 alkyl, C5-C10 heteroaryl and (C5-C10 heteroaryl) C1-C2 alkyl;
R1″ is a substituent selected from the following group: halogen, OH, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, —NH2, (C1-C6 alkyl)—NH— and —N(C1-C6 alkyl)2.
8. The compound as claimed in claim 2, characterized in that R1′ is
Figure US08969373-20150303-C00109
9. The compound as claimed in claim 2, characterized in that R1 linking covalently with R3 together forms a C5 alkane chain.
10. The compound as claimed in claim 2, characterized in that R4 is C1-C10 alkoxycarbonyl, (C1-C10 alkyl)—NHCO, (C1-C10 alkyl)2NCO, 6-8 membered aryl, 5-8 membered heteroaryl having 1-3 heteroatoms selected from O, N and S or formyl substituted by 3˜7 membered cycloalkyl, 4-6 membered heterocycl having 1-3 heteroatoms selected from O,S and N or cycloalkoxy, which can be substituted by 1 or more R4′;
R4′ is a substituent selected from the following group: halogen, OH, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, —NH2, (C1-C6alkyl)—NH— and —N(C1-C6 alkyl)2, (C1-C6 alkyl)—SO2—.
11. The compound as claimed in claim 2, characterized in that R4 is
Figure US08969373-20150303-C00110
wherein, Rx and Ry independently is F, Cl, C1-C6 alkyl or C1-C6 alkoxyl, Rz is C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 alkylformyl or (C1-C6alkyl)—SO2—.
12. The compound as claimed in claim 1, characterized in that the compound is
Figure US08969373-20150303-C00111
Figure US08969373-20150303-C00112
Figure US08969373-20150303-C00113
Figure US08969373-20150303-C00114
Figure US08969373-20150303-C00115
Figure US08969373-20150303-C00116
Figure US08969373-20150303-C00117
Figure US08969373-20150303-C00118
Figure US08969373-20150303-C00119
Figure US08969373-20150303-C00120
Figure US08969373-20150303-C00121
Figure US08969373-20150303-C00122
Figure US08969373-20150303-C00123
Figure US08969373-20150303-C00124
13. The compound as claimed in claim 4, characterized in that Ar is a 6 membered aryl or a 5˜6 membered heteroaryl which is substituted optionally by 1 or more RAr; wherein, RAr is selected from the following substituent group: halogen, amino, C1-C6 alkyl, C1-C6alkoxyl, C1-C6 hydroxyalkyl and (C1-C6) alkylamido.
14. The compound as claimed in claim 4, characterized in that Rm is a substituent which can be substituted by 1˜3 Rm′ selected from the following group: C1-C8 alkyl, N≡C—(C1-C6) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) cycloalkyl, (C3-C7 cycloalkyl) (C1-C6) alkyl, and 5˜6 membered aryl or heteroaryl having 1-2 heteroatom(s) independently selected from N, O, S; Rm′ is a substituent selected from the following group: halogen, (C1-C6) alkyl substituted optionally by (C1-C6)alkyl-O— or (C3-C6)cycloalkyl-O—, (C1-C6) haloalkyl, (C3-C7)cycloalkyl, (C1-C6)alkyl-O—, heteroaryl, —NH2, (C1-C4 alkyl)NH— and (C1-C4 alkyl)2N—.
15. The compound as claimed in claim 4, characterized in that R1′ is a substituent which can be substituted by 1 or more R1″ selected from the following group: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-8 membered aryl, (6-8 membered aryl) C1-C2 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl) C1-C2 alkyl, C3-C7 cycloalkenyl, (C3-C7 cycloalkenyl) C1-C2 alkyl, 4-6 membered heterocycl having 1-3 heteroatoms selected from O, S, and N, (4-6 membered heterocycl having 1-3 heteroatoms selected from O, S and N) C1-C2 alkyl, C5-C10 heteroaryl and (C5-C10 heteroaryl) C1-C2 alkyl;
R1″ is a substituent selected from the following group: halogen, OH, CN, C1-X6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, —NH2, (C1-C6 alkyl)—NH— and —N(C1-C6 alkyl)2.
16. The compound as claimed in claim 4, characterized in that R1′ is
Figure US08969373-20150303-C00125
17. The compound as claimed in claim 4, characterized in that R1 linking covalently with R3 together forms a C5 alkane chain.
18. The compound as claimed in claim 4, characterized in that R4 is C1-C10 alkoxycarbonyl, (C1-C10 alkyl)—NHCO, (C1-C10 alkyl)2NCO, 6-8 membered aryl, 5-8 membered heteroaryl having 1-3 heteroatoms selected from O, N and S or formyl substituted by 3˜7 membered cycloalkyl, 4-6 membered heterocycl having 1-3 heteroatoms selected from O, S, and N or cycloalkoxy, which can be substituted by 1 or more R4′;
R4′ is a substituent selected from the following group: halogen, OH, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, —NH2, (C1-C6 alkyl)—NH— and —N(C1-C6 alkyl)2, (C1-C6 alkyl)—SO2—.
19. The compound as claimed in claim 4, characterized in that R4 is
Figure US08969373-20150303-C00126
wherein, Rx and Ry independently is F, Cl, C1-C6 alkyl or C1-C6 alkoxyl, Rz is C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 alkylformyl or (C1-C6 alkyl)—SO2—.
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US20090286814A1 (en) * 2008-05-16 2009-11-19 Taigen Biotechnology Co., Ltd. Hcv protease inhibitors
US20110065737A1 (en) * 2009-09-15 2011-03-17 Taigen Biotechnology Co., Ltd. Hcv protease inhibitors
US20110178107A1 (en) * 2010-01-20 2011-07-21 Taigen Biotechnology Co., Ltd. Hcv protease inhibitors

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JP5945837B2 (en) 2016-07-05
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